GLUCOSE METABOLISM AND THE DEFAULT MODE NETWORK IN HEALTH AND DISEASE

描述（由申请人提供）：本提案的主要假设是氧化磷酸化之外的脑葡萄糖代谢（我们称之为糖酵解）在健康和疾病的脑功能中起着重要作用。我们对糖酵解的兴趣源于我们在提出这一建议之前所做的几项观察。糖酵解占成人大脑代谢葡萄糖的12 - 15%。这种糖酵解的很大一部分发生在被称为大脑默认模式网络（DMN）的大脑区域网络中。DMN由内侧和外侧顶叶皮质、背侧和腹侧内侧前额叶皮质以及内侧颞叶皮质组成。值得注意的是，它在静息状态下更活跃，是大脑功能组织的核心，在任何一组大脑区域中具有最高的糖酵解率，并且特别容易患阿尔茨海默病。因为糖尿病已经成为阿尔茨海默病的一个重要的风险因素，所以我们把这两种疾病放在一起考虑，葡萄糖代谢如何不仅可以定义大脑中特定的区域网络，还可以增加这些区域对阿尔茨海默病的脆弱性。在提出的实验中，我们询问脑糖酵解和静息状态功能连接如何受到年龄、睡眠和葡萄糖稳态和胰岛素敏感性的系统性改变的调节。我们特别假设慢性高血糖和胰岛素抵抗以及睡眠剥夺会增加脑区域（如DMN）的糖酵解和A¿释放，这些区域严重依赖糖酵解，导致A¿沉积增加并加速AD的发病。项目1和项目2将探讨AD高危人群（老年人和2型糖尿病患者）葡萄糖稳态和胰岛素敏感性的系统性改变如何调节脑糖酵解和DMN的功能连接

DESCRIPTION (provided by applicant): The overarching hypothesis in this proposal is that brain glucose metabolism outside of oxidative phosphorylation (which we refer to as glycolysis) plays an important role in brain function in health and disease. Our interest in glycolysis arose from several observations made by us leading up to this proposal. Glycolysis accounts for 12 to15% of glucose metabolized by the adult human brain. A large fraction of this glycolysis occurs in a network of brain areas dubbed the brain's default mode network (DMN). The DMN consists of areas in medial and lateral parietal cortices, dorsal and ventral medial prefrontal cortex and the medial temporal cortices. It is noteworthy because it is more active in the resting state, is central to the functional organization of the brain, has the highest rate of glycolysis o any group of brain areas and is uniquely vulnerable to Alzheimer's disease. Because diabetes has emerged as a significant risk factor for Alzheimer's disease caused us to consider these two diseases together in terms of how glucose metabolism might not only serve to define a specific network of areas in the brain but also increase the vulnerability of these areas to Alzheimer's disease. In the experiments proposed, we ask how brain glycolysis and resting-state functional connectivity are regulated by age, sleep and systemic alterations in glucose homeostasis and insulin sensitivity. We specifically hypothesize that chronic hyperglycemia and insulin resistance as well as sleep deprivation increase glycolysis and A¿ release in brain areas, such as the DMN, that are heavily reliant on glycolysis, leading to increased A¿ deposition and accelerating the pathogenesis of AD. Project 1 and 2 will explore how brain glycolysis and functional connectivity in the DMN are regulated by systemic alterations in glucose homeostasis and insulin sensitivity in populations at risk for AD (older individuals and people with T2DM), and experiments in Project 3 will enable ideas tested in Projects 1 and 2 to be taken from the systems neuroscience level to the cellular and molecular level.