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

随着我们社会的老龄化，老龄化对生活质量的影响变得越来越重要。正常“健康”衰老的一个共同特征是认知能力逐渐下降。这种下降的开始和速度因人而异，我们目前对这种情况的发生方式和原因知之甚少。我们将通过测量小鼠在正常衰老过程中大脑结构和功能的变化来做到这一点。这是发展任何治疗衰老策略的重要一步。在人类中，通常在前额皮质中观察到与年龄相关的脑容量变化。这个大脑区域在塑造我们的个性和控制决策等“执行”功能方面起着重要作用。这些执行功能的丧失可能是与年龄相关的认知能力下降的一些最具破坏性方面的基础。到目前为止，从非侵入性人脑成像研究中获得的数据还无法提供有关这些变化本质的任何机制见解。因此，如果我们要更好地了解衰老过程的生物学原理，动物研究是至关重要的。在这个提议中，我们将标记从大脑不同区域到达前额皮质的神经纤维，包括海马体——记忆存储的关键结构。我们将使用一种新方法来测量这些不同连接的强度，这种方法允许我们用蓝光照射神经纤维来激活它们。我们将能够测量在正常衰老过程中神经纤维的排列和强度是如何变化的。重要的是，在我们记录了需要前额叶皮层活跃的行为任务（例如决策任务）期间大脑的电活动后，这些大脑映射技术将被应用。通过这种方式，我们将绘制出前额叶皮层神经细胞的结构和功能，并直接测量大脑功能的变化是否导致认知能力受损。重要的是，我们将比较年龄匹配的动物的大脑结构，这些动物有和没有表现出认知能力下降。最后，我们使用分子生物学工具引入一种毒素，阻止前额皮质细胞之间的神经交流。通过逐渐减少前额叶皮层的神经交流量，我们试图验证前额叶皮层连通性下降是认知能力下降的基础。我们的三个实验室在探索正常衰老过程中前额皮质的结构和功能变化方面处于独特的地位。这项合作的多学科性质将提供来自单个脑细胞和神经网络的数据，以揭示导致衰老的基本生物学机制。这个提议的一个特别的焦点是理解为什么衰老的速度在个体之间似乎是不同的，为了做到这一点，我们将研究和比较有和没有表现出认知能力下降的动物的大脑。我们将探索健康老龄化与大脑连接结构和功能的高度稳健性相关的可能性。另外，健康老龄化的特点可能是代偿性变化，这种变化可以保持认知功能，保护大脑免受与年龄相关的脆弱。

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.