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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 功能磁共振波谱（fMRS）允许非侵入性测量人脑中的代谢物浓度，包括由神经传递活动变化引起的变化。然而，有限的空间和时间分辨率的fMRS不允许特定的测量 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 代谢需要数学模型的公式化和应用。在本研究中，我们利用Simpson等人（2007）引入的数学模型，从Mangia等人（2007 a）在超高磁场下获得的人体fMRS数据中深入了解体内区室化代谢。该模型模拟了理论皮层切片中的脑葡萄糖和乳酸水平。使用实验确定的浓度和各自的转运蛋白的催化活性，我们计算流入和出口的葡萄糖和乳酸在内皮细胞，星形胶质细胞和神经元。 然后，我们改变神经元和星形胶质细胞的葡萄糖和乳酸利用能力，直到密切对应， 在体内和模拟的葡萄糖和乳酸水平之间观察到。模拟的结果表明，当利用葡萄糖转运能力的文献值时，fMRS数据与神经元的乳酸盐输出和星形胶质细胞的乳酸盐输入一致，这是一种可以被称为神经元-星形胶质细胞乳酸盐穿梭的机制。可以模拟乳酸从星形胶质细胞到神经元的穿梭，但 这需要星形胶质细胞葡萄糖转运能力增加12倍，并且需要神经元不响应于具有增加的糖酵解的激活，

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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,