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COUPLING OF METABOLIC PROCESSES AND FUNCTIONAL ACTIVITY IN BRAIN

代谢过程与大脑功能活动的耦合

基本信息

批准号：
6290564
负责人：
LOUIS SOKOLOFF
金额：
--
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6290564
关键词：
brain metabolism fatty acid metabolism glia glucose metabolism glycogen laboratory rat lactates oxygen consumption potassium

项目摘要

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

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，以便将葡萄糖完全氧化成氧气和水。最近，这一观点受到了挑战，因为已发表的 PET 研究结果表明，在感觉刺激过程中，消耗的葡萄糖多于耗氧量。这些报告引发了一种流行但推测性的观点，即大脑的功能活动仅由来自糖酵解而非氧化代谢的能量支持。在氧气供应有限的情况下，这是可以预料到的，但在氧气充足的情况下发生这种情况违反了能量代谢的传统概念。因此，我们在清醒大鼠体内检查了在功能激活导致葡萄糖消耗增加的条件下[14C]葡萄糖的大脑代谢。测量了每个功能状态的时间结束时脑动静脉O2、葡萄糖和乳酸的差异以及大脑中乳酸、糖原和葡萄糖的总水平和14C标记水平。在 K+- 刺激代谢活动期间，脑乳酸池的 14C- 标记增加了 3 倍。大脑吸收的大约 20% 的葡萄糖以乳酸的形式流失到血液中，并且类似数量的葡萄糖肯定已经从激活的组织运输到了其他大脑区域。因此，大脑内中间代谢物的运输可能是广泛的，这是一个新的、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，乳酸在大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率超过了耗氧量的化学计量当量。此外，大脑中主要位于星形胶质细胞中的糖原水平在感觉功能激活期间减少。然而，在从感觉刺激恢复期间，氧/葡萄糖比率上升到比完全化学计量高得多的水平，表明氧消耗量大于同等葡萄糖利用率。因此，这些结果表明功能活性仅依赖于糖酵解而不依赖于氧化代谢是不正确的。氧代谢和葡萄糖代谢之间明显的脱钩只是暂时的、暂时的。过量的葡萄糖利用导致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为二氧化碳和水。该作品的手稿已出版或正在印刷中。该项目现已停止，因为从事该项目的专业人员已经离开实验室，现在正在新地点继续这些研究。出版物Madsen, P. L., Cruz, N. F., Sokoloff, L., 和 Dienel, G. A. 脑氧/葡萄糖比率在感觉刺激期间较低，并在恢复期间升至高于正常水平：刺激期间过量的葡萄糖消耗不能由脑组织中的乳酸流出或积累来解释。 J·塞雷布。血流代谢。 19:393-400； 1999.-局部脑血流耗氧腺苷受体