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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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，

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,