Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging
Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging
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DOI：
10.1098/rstb.1999.0471
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发表时间：
1999-07-29
影响因子：
6.3
通讯作者：
Pellerin, L
中科院分区：
文献类型：
--
作者：
Magistretti, PJ;Pellerin, L
尽管功能性脑成像技术取得了惊人的进展，但这些技术检测到的信号背后的细胞和分子机制在很大程度上仍然是未知的。功能成像的基本生理学原理由神经元活动与血流和能量代谢的相关局部增加之间存在的紧密耦合来表示。正电子发射断层扫描（PET）信号检测与神经元活动相关的血流量、耗氧量和葡萄糖使用;血氧的程度目前被认为有助于功能性磁共振成像检测到的信号，而磁共振波谱（MRS）识别某些代谢中间产物（如葡萄糖或乳酸盐）的活动依赖性外观的时空模式。最近的研究，包括纯化制剂中神经递质调节的代谢通量和参与能量代谢的酶和转运蛋白的细胞定位分析，以及体内微透析和MRS方法，已经确定了神经递质谷氨酸和星形胶质细胞（一种特定类型的神经胶质细胞）作为突触活动与能量代谢耦合的关键要素。星形胶质细胞处于理想的位置，可以感知突触活动的增加，并将其与能量代谢相结合。事实上，它们拥有覆盖实质内毛细血管表面的专门过程，这表明星形胶质细胞可能是普遍葡萄糖摄取的可能位点。其他星形胶质细胞过程包裹在突触接触周围，这些突触接触具有神经递质的受体和再摄取位点。谷氨酸刺激葡萄糖摄取到星形胶质细胞。这种作用是由这些细胞上存在的特异性谷氨酸转运蛋白介导的。这些转运蛋白的活性与谷氨酸的突触释放紧密耦合，并操作谷氨酸从细胞外空间的清除，由Na+的电化学梯度驱动。星形胶质细胞对谷氨酸的这种Na+依赖性摄取触发了涉及Na+/K+-ATP酶的分子事件级联，导致星形胶质细胞对葡萄糖的糖酵解加工和乳酸的释放。这个过程的化学计量是这样的，对于一个谷氨酸分子与三个Na+离子，一个葡萄糖分子进入星形胶质细胞，两个ATP分子通过有氧糖酵解产生，两个乳酸分子被释放。在星形胶质细胞内，一个ATP分子为“泵的一转”提供燃料，而另一个ATP分子提供通过谷氨酰胺合酶将谷氨酸转化为谷氨酰胺所需的能量。从结构和功能研究中积累的证据表明，在有氧条件下，乳酸可能是激活的神经元的优选能量底物。事实上，在氧气存在下，乳酸盐转化为丙酮酸盐，丙酮酸盐可以通过三羧酸循环和相关的氧化磷酸化处理，以产生每个乳酸盐分子17个ATP分子。这些数据表明，在激活过程中，大脑可能会短暂地诉诸于发生在星形胶质细胞中的有氧糖酵解，然后由神经元氧化乳酸。所提出的模型提供了将突触活动与葡萄糖使用耦合的直接机制，并且与以下概念一致，即在用F-18-脱氧葡萄糖（DG）-PET的生理激活期间检测到的信号可能主要反映：该结论并不质疑基于2-DG的技术的有效性，相反，它为这些功能性脑成像技术提供了细胞和分子基础。
Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood flow and energy metabolism. Positron emission tomography (PET) signals detect blood flow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identifies the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic fluxes in purified preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identified the neurotransmitter glutamate and astrocytes, a specific type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This effect is mediated by specific glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na+. This Na+-dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na+/K+-ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na+ ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one 'turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule. These data suggest that during activation the brain may transiently resort to aerobic glycolysis occurring in astrocytes, followed by the oxidation of lactate by neurons. The proposed model provides a direct mechanism to couple synaptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with F-18-deoxyglucose (DG)-PET may reflect predominantly; uptake of the tracer into astrocytes.This conclusion does not question the validity of the 2-DG-based techniques, rather it provides a cellular and molecular basis for these functional brain imaging techniques.