Neurotransmitter Systems and their role in Cognitive and Metabolic Reserve in Ageing

在健康老龄化过程中，神经网络结构和功能有所退化，但个体差异表现出一定程度的中度认知衰退。先前的研究已经得出结论，胆碱能基底前脑（ChBF）萎缩的变化会影响认知储备的程度（即从一个临界点开始的缓冲的大小，超过这个临界点，能力就会减弱）。同样，环境因素也会影响代谢储备水平，即细胞功能与其最大代谢能力相比的程度。这进一步导致抵抗细胞功能障碍的个体差异，这最终会导致认知能力的保留。本研究旨在探讨胆碱能投射促进脑白质替代连接的机制，以保持认知网络功能。它还将探索衰老过程中代谢和认知储备的个体差异，以及它们与胆碱能和其他递质系统的关系，以期深入了解其机制并阐明潜在的治疗靶点。这项工作将包括分析人类MRI扫描和认知测试，以确定ChBF萎缩，功能连接和认知之间的关系。随着新技术的出现，这项工作可以扩展到其他发射机系统；例如，神经黑色素加权MRI利用磁化转移原理来量化人类多巴胺能和去肾上腺素能核的萎缩。此外，本项目将通过大鼠模型研究胆碱能系统与代谢储备之间的关系，在注射代谢促进亚甲基蓝前后采用MRI和组织学技术，研究潜在的储备机制。

During healthy ageing, network structure and function deteriorates but individual differences appear to moderate cognitive decline to some extent. Previous work has concluded that variations in cholinergic basal forebrain (ChBF) atrophy influences the degree of cognitive reserve, (i.e. the magnitude of a buffer from a critical point, beyond which competence diminishes). Similarly, environmental factors contribute to the level of metabolic reserve, which is the extent of cell functioning compared to its maximum metabolic capacity. This leads to further individual differences in resisting cell dysfunction, which can ultimately engender retention of cognitive faculties.This work aims to investigate the mechanisms allowing cholinergic projections to promote alternative white matter connections, in order to preserve cognitive network function. It will also explore individual differences in metabolic and cognitive reserve in ageing, and how they relate to cholinergic and other transmitter systems, with the intention of gaining insight into their mechanisms and illuminating potential therapy targets. This work will include analysis of human MRI scans and cognitive testing to determine how ChBF atrophy, functional connectivity, and cognition are related. As new techniques emerge, this work can be extended to other transmitter systems; for instance, neuromelanin-weighted MRI utilises magnetisation transfer principles to quantify atrophy of dopaminergic and noradrenergic nuclei in humans. Furthermore, this project will examine underlying reserve mechanisms by using rat models to study the relationship between the cholinergic system and metabolic reserve, employing MRI before and after injections of metabolism-boosting methylene blue, and histological techniques.