GLUCOSE METABOLISM AND THE DEFAULT MODE NETWORK IN HEALTH AND DISEASE

描述(申请人提供)：这项建议中的首要假设是，氧化磷酸化(我们称为糖酵解)以外的大脑葡萄糖代谢在健康和疾病的大脑功能中发挥着重要作用。我们对糖酵解的兴趣源于我们在这一提议之前所做的几项观察。糖酵解占成人大脑代谢的葡萄糖的12%到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、背侧和腹侧前额叶内侧皮质以及内侧颞叶皮质组成。值得注意的是，它在休息状态下更活跃，是大脑功能组织的核心，在任何大脑区域具有最高的糖酵解率，并且特别容易患上阿尔茨海默氏症。由于糖尿病已经成为阿尔茨海默氏症的一个重要风险因素，促使我们将这两种疾病放在一起考虑，考虑到葡萄糖代谢如何不仅可以定义大脑中特定区域的网络，还会增加这些区域对阿尔茨海默氏症的易感性。在提出的实验中，我们询问了大脑糖酵解和静息状态功能连接是如何受到年龄、睡眠以及全身葡萄糖稳态和胰岛素敏感性变化的调节的。我们特别假设，慢性高血糖和胰岛素抵抗以及睡眠剥夺增加了严重依赖糖酵解的大脑区域(如DMN)的糖酵解和A？释放，导致A？沉积增加，加速了AD的发病。项目1和2将探索在阿尔茨海默病(AD)高危人群(老年人和T2 DM患者)中，DMN中的大脑糖酵解和功能连接如何受到葡萄糖稳态和胰岛素敏感性的系统性变化的调节，以及 项目3中的实验将使项目1和2中测试的想法能够从系统神经科学层面延伸到细胞和分子层面。

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.