Relating changes in synaptic function to cognitive decline during normal healthy ageing

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As our society grows older, the consequences of ageing on quality of life becomes ever more important. A common feature of normal 'healthy' ageing is a gradual cognitive decline. The onset and rate of this decline differs between individuals and we currently know very little about how and why this is the case. We will do this by measuring the changes in both brain structure and function that take place during normal ageing in mice. This is a vital step in the development of any therapeutic strategies for the management of ageing. In humans, age-related changes in brain volume have commonly been observed in the prefrontal cortex. This brain area plays an important role in shaping our personality and controls 'executive' functions such as decision-making. A loss of these executive functions is likely to underlie some of the most damaging aspects of age-related cognitive decline. Until now, data obtained from non-invasive human brain imaging studies have been unable to provide any mechanistic insight into the nature of the changes. Animal studies are, therefore, vital if we are to better understand the biology of the ageing process.In this proposal we will label nerve fibres arriving in the prefrontal cortex from different regions of the brain, including the hippocampus - a structure crucial in memory storage. We will measure the strength of these different connections using a new method that allows us to activate nerve fibres by illuminating them with blue light. We will be able to measure how both the arrangement and strength of nerve fibres change during the course of normal ageing. Importantly, these brain mapping techniques will be applied after we have recorded the electrical activity directly in the brain during behavioural tasks that require the prefrontal cortex to be active (e.g. a decision making task). In this way we will map the structure and function of nerve cells in the prefrontal cortex and directly measure whether changes in brain function are responsible for impaired cognitive performance. Importantly, we will compare the brain structure in in age-matched animals that do and do not exhibit cognitive decline. Finally, we use molecular biological tools to introduce a toxin that blocks nerve communication between cells in the prefrontal cortex. By gradually decreasing the amount of nerve communication in the prefrontal cortex, we seek to test the hypothesis that decreased connectivity in the prefrontal cortex underlies cognitive decline. Our three laboratories are in a unique position to explore structural and functional changes in the prefrontal cortex during normal ageing. The multidisciplinary nature of this collaboration will provide data from single brain cells and neuronal networks in order to reveal the fundamental biological mechanisms responsible for the ageing. A particular focus of this proposal is to understand why the rate of ageing appears to differ between individuals, and to do this we will study and compare the brains of animals that do and do not exhibit cognitive decline. We will explore the possibility that healthy ageing is associated with a high degree of robustness in terms of the structure and function of brain connectivity. Alternatively, healthy ageing may well be characterized by compensatory changes that can preserve cognitive function and protect the brain against age-related frailty.