COUPLING OF METABOLIC PROCESSES AND FUNCTIONAL ACTIVITY IN BRAIN

代谢过程与大脑功能活动的耦合

• 批准号: 6111183
• 负责人: LOUIS SOKOLOFF
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 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/6111183
• 关键词: brain metabolism; fatty acid metabolism; glia; glucose metabolism; glycogen; laboratory rat; lactates; oxygen consumption; potassium

It has been generally believed that the brain's energy demands were 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 because of PET studies reporting that glucose is used in excess of equivalent oxygen consumption during cognitive challenges or sensory stimulation. This has led to the now popular speculation that functional activity in brain is supported by energy derived from glycolysis and litt,e if at all, from oxidative metabolism. Under conditions of limited oxygen supply, this would be expected, but for this to happen in the presence of adequate O2 violates traditional concepts of energy metabolism. We have, therefore, examined in conscious rats in vivo the metabolism of [14C]glucose in rat brain 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, 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 glucose metabolism is only temporal; the excess glucose utilization leads to accumulation of glucose metabolites in intermediate pools during functional activation which are then oxidized further to CO2 and H2O over an extended period of time during recovery. Manuscripts on this work have been published or are in press. This project is now discontinued here because the professional staff members who were working on it have left the laboratory and are now continuing these studies at their new locations. Publications Dienel, G.A., Cruz, N.F., Adachi, K., Sokoloff, L., and Holden, J.E. (1997) Determination of local brain glucose level with [14C]methylglucose: Effects of glucose supply and demand. Am J. Physiol. (Endocrinol. Metab. 36), 273: E839-E849. Madsen, P.L., Cruz, N.F., Sokoloff, L, and Dienel, G.A. (In press) 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 lactate efflux from or accumulation in brain tissue. J. Cereb. Blood Flow Metab. (Accepted August 14, 1998).

人们普遍认为大脑的能量 通常通过消耗氧气来满足需求 化学计量的葡萄糖用于完全氧化 葡萄糖转化为氧气和水。这种信念最近受到挑战 因为 PET 研究报告葡萄糖的使用量超过 认知挑战期间的等效耗氧量或 感官刺激。这引发了现在流行的猜测 大脑的功能活动是由来自于的能量支持的 糖酵解和氧化代谢很少（如果有的话）。在下面 在氧气供应有限的条件下，这是可以预料到的，但对于 在有足够氧气存在的情况下发生这种情况违反了传统 能量代谢的概念。因此，我们研究了 清醒大鼠体内[14C]葡萄糖在大鼠脑内的代谢 在葡萄糖消耗增加的条件下 功能激活。脑动静脉 O2 葡萄糖，以及 乳酸差异以及乳酸总水平和 14C 标记水平， 每个周期结束时大脑中的糖原和葡萄糖 测量功能状态。 14C-脑乳酸标记 在 K+- 刺激代谢活动期间，池增加了 3 倍。 大脑吸收的葡萄糖大约有20%流失到血液中 作为乳酸，并且类似数量必须是从 激活其他大脑区域的组织。因此，贩运 大脑内的中间代谢物可以是广泛的，一种新的， 意外的发现。感觉刺激期间和之后 乳酸在大脑中的积累和血液中的损失都很大 即使氧/葡萄糖摄取比降低，也较小， 表明葡萄糖利用率超过化学计量 相当于刺激期间的耗氧量 。此外，大脑中糖原的水平主要集中在 星形胶质细胞在感觉功能激活期间减少。 然而，在从感觉刺激恢复期间， 氧/葡萄糖比上升到比之前高得多的水平 完整的化学计量，表明耗氧量更大 比等量的葡萄糖利用率。因此，这些结果表明 功能活性仅取决于糖酵解是不正确的 而不是氧化代谢。之间明显的脱钩 氧糖代谢只是暂时的；过量的葡萄糖 利用导致葡萄糖代谢物的积累 功能激活期间的中间池，然后 在较长时间内进一步氧化成CO2和H2O 恢复期间。本作品的手稿已发表或 正在印刷中。该项目现已停止，因为 负责该项目的专业工作人员已离开 实验室，现在正在他们的新实验室继续这些研究 地点。出版物 Dienel, G.A.、Cruz, N.F.、Adachi, K.、 Sokoloff, L. 和 Holden, J.E. (1997) 局部大脑的测定 [14C]甲基葡萄糖的血糖水平：葡萄糖供应的影响 和需求。我是 J. Physiol。 （内分泌代谢物 36），273： E839-E849。 Madsen, P.L.、Cruz, N.F.、Sokoloff, L 和 Dienel， GA （正在出版）感觉期间脑氧/葡萄糖比率较低 刺激并在恢复期间升高至高于正常水平：葡萄糖过量 刺激期间的消耗不由乳酸负责 从脑组织中流出或积聚。 J·塞雷布。血流（量 代谢物。 （1998 年 8 月 14 日接受）。