COUPLING OF METABOLIC PROCESSES AND FUNCTIONAL ACTIVITY IN BRAIN

人们普遍认为，大脑的能量需求通常是通过消耗化学计量的氧气和葡萄糖来满足的，以使葡萄糖完全氧化为氧气和水。这一信念最近受到了挑战，因为发表的PET研究结果表明，在感觉刺激过程中，葡萄糖的使用量超过了氧气消耗量。这些报告激起了一种流行的、但却是推测的信念，即大脑的功能活动只由糖酵解产生的能量支持，而不是由氧化代谢提供。在氧气供应有限的情况下，这是意料之中的，但在氧气充足的情况下发生这种情况违反了能量新陈代谢的传统概念。因此，我们在清醒的大鼠体内检测了在功能激活增加葡萄糖消耗的条件下[14C]葡萄糖的大脑代谢。在每个功能状态的周期结束时，测量脑动静脉O2、葡萄糖和乳酸的差值以及脑组织中总的和14C标记的乳酸、糖原和葡萄糖的水平。在K+刺激的代谢活动中，脑乳酸池的14C标记增加了3倍。大脑吸收的葡萄糖中约有20%以乳酸的形式流失到血液中，类似数量的葡萄糖肯定是从激活的组织运输到大脑的其他区域。因此，中间代谢物在大脑内的运输可能是广泛的，这是一个新的和意想不到的发现。在感觉刺激期间和之后，即使氧/葡萄糖摄取比降低，乳酸在脑中的积累和血液中的损失也要小得多，这表明在刺激期间葡萄糖的利用超过了化学计量当量的氧气消耗。此外，在感觉功能激活过程中，主要定位于星形胶质细胞的脑糖原水平也会降低。然而，在从感觉刺激中恢复的过程中，氧/葡萄糖比率上升到比完全化学计量比高得多的水平，这表明氧气消耗比同等的葡萄糖利用更大。因此，这些结果表明，仅依赖糖酵解而不依赖氧化代谢的功能激活是不正确的。氧和葡萄糖代谢之间的明显解偶联只是暂时的；过量的葡萄糖利用导致在功能激活期间葡萄糖代谢物在中间池中积累，然后在恢复期间的较长时间内进一步氧化成二氧化碳和水。关于这部作品的手稿已经出版或正在印刷中。该项目现已停止，因为从事该项目的专业工作人员已离开实验室，目前正在新的地点继续进行这些研究。出版物Madsen，P.L.，Cruz，N.F.，Sokoloff，L.和Dienel，G.大脑氧/葡萄糖比率在感觉刺激期间较低，在恢复期间高于正常水平：刺激期间过量的葡萄糖消耗不是乳酸从脑组织外流或在脑组织中积累的原因。J·雷伯。血液流动Metab。19：393-400；1999。-局部脑血流耗氧量腺苷受体

It has been generally believed that the brains energy demands are normally met by the consumption of oxygen and glucose in stoichiometric amounts for the complete oxidation of glucose to oxygen and water. This belief was recently challenged on the basis of results of published PET studies suggesting that more glucose is used than can be accounted for by oxygen consumption during sensory stimulation. These reports provoked a popular but speculative belief that functional activity in brain is supported only by by energy derived from glycolysis and not from oxidative metabolism. Under conditions of limited oxygen supply, this would be expected, but for this to happen in the presence of adequate oxygen violates traditional concepts of energy metabolism. We, therefore, examined in conscious rats in vivo the brains metabolism of [14C]glucose under conditions in which glucose consumption was increased by functional activation. Cerebral arteriovenous O2, glucose, and lactate differences and total and 14C-labeled levels of lactate, glycogen, and glucose in the brain at the end of the period for each functional state were measured. 14C- labeling of the brain lactate pool was increased 3-fold during K+- stimulated metabolic activity. About 20% of the glucose taken up by brain was lost to the blood as lactate, and similar quantities must have been transported from activated tissue to other brain regions. Thus, trafficking of intermediary metabolites within the brain can be extensive, a new and unexpected finding. During and following sensory stimulation lactate accumulation in the brain and loss to the blood were much smaller even though the oxygen/glucose uptake ratio was reduced, indicating that glucose utilization exceeded the stoichiometric equivalent of the oxygen consumption during the stimulation period. Also, brain levels of glycogen, which is localized mainly in astroglial cells, was diminished during sensory functional activation. During recovery from the sensory stimulation, however, the oxygen/glucose ratio rose to much higher levels that that for complete stoichiometry, indicating greater oxygen consumption than equivalent glucose utilization. These results, therefore, show that it is not true that functional activaty depends only on glycolytic and not oxidative metabolism. The apparent uncoupling between oxygen and glucose metabolism is only temporal and temporary; the excess glucose utilization leads to accumulation of glucose metabolites in intermediate pools during functional activation which are then oxidized further to carbon dioxide ands water over an extended period of time during recovery. Manuscripts on this work have been published or are in press. This project is now discontinued because the professional staff members who were working on it have left the laboratory and are now continuing these studies at their new locations. PublicationsMadsen, P. L., Cruz, N. F., Sokoloff, L., and Dienel, G. A. Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: Excess glucose consumption during stimulation is not accounted for by lactateefflux from or accumulation in brain tissue. J. Cereb. Blood Flow Metab. 19:393-400; 1999. - local cerebral blood flow oxygen consumption adenosine receptors