THE IN VIVO NEURON-TO-ASTROCYTE LACTATE SHUTTLE IN HUMAN BRAIN

人脑中的体内神经元到星形胶质细胞的乳酸穿梭

• 批准号: 8362881
• 负责人: Silvia Mangia
• 金额: $ 1.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362881
• 关键词: Astrocytes; Brain; Carrier Proteins; Data; Drug Formulations; Endothelium; Funding; Glucose; Glycolysis; Grant; Human; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Metabolism; Modeling; NMR Spectroscopy; National Center for Research Resources; Neurons; Principal Investigator; Research; Research Infrastructure; Resolution; Resources; Simulate; Slice; Source; United States National Institutes of Health; Variant; cell type; cost; glucose transport; in vivo; insight; magnetic field; mathematical model; neurotransmission; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Functional magnetic resonance spectroscopy (fMRS) allows the non-invasive measurement of metabolite concentrations in the human brain, including changes induced by variations in neurotransmission activity. However, the limited spatial and temporal resolution of fMRS does not allow specific measurements of metabolites in different cell types. Thus, the analysis of fMRS data in the context of compartmentalized metabolism requires the formulation and application of mathematical models. In the present study we utilized the mathematical model introduced by Simpson et al. (2007) to gain insights into compartmentalized metabolism in vivo from the fMRS data obtained in humans at ultra high magnetic field by Mangia et al. (2007a). This model simulates brain glucose and lactate levels in a theoretical cortical slice. Using experimentally determined concentrations and catalytic activities for the respective transporter proteins, we calculate inflow and export of glucose and lactate in endothelium, astrocytes, and neurons. We then vary neuronal and astrocytic glucose and lactate utilization capacities until close correspondence is observed between in vivo and simulated glucose and lactate levels. The results of the simulations indicate that, when literature values of glucose transport capacity are utilized, the fMRS data are consistent with export of lactate by neurons and import of lactate by astrocytes, a mechanism that can be referred to as a neuron-to-astrocyte lactate shuttle. A shuttle of lactate from astrocytes to neurons could be simulated, but this required the astrocytic glucose transport capacity to be increased by 12-fold, and required that neurons not respond to activation with increased glycolysis,

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 功能磁共振波谱(FMRS)可以非侵入性地测量人脑中的代谢物浓度，包括由神经传递活动的变化引起的变化。然而，FMR有限的空间和时间分辨率不允许进行特定的测量 不同细胞类型的代谢物。因此，在划分的背景下对FMRS数据进行分析 新陈代谢需要数学模型的表述和应用。在本研究中，我们使用了Simpson等人介绍的数学模型。(2007)从Mangia等人在超高磁场下获得的人体FMRS数据中获得对体内分区新陈代谢的见解。(2007a)。这个模型在理论上的大脑皮层切片中模拟大脑中的葡萄糖和乳酸水平。使用实验确定的各自转运蛋白的浓度和催化活性，我们计算了内皮细胞、星形胶质细胞和神经元中葡萄糖和乳酸的流入和输出。 然后，我们改变神经元和星形细胞的葡萄糖和乳酸的利用能力，直到密切对应 观察体内和模拟的葡萄糖和乳酸水平。模拟结果表明，当利用葡萄糖转运能力的文献值时，FMRS的数据与神经元输出乳酸和星形胶质细胞输入乳酸的机制是一致的，这种机制可以称为神经元到星形胶质细胞的乳酸穿梭。可以模拟乳酸从星形胶质细胞到神经元的穿梭，但 这需要将星形胶质细胞的葡萄糖运输能力提高12倍，并要求神经元不会因糖酵解增加而对激活做出反应，