Regional Cerebral Circulation And Metabolism

这是一个综合性项目，涵盖了各种研究的发展，验证，完善和应用的方法，以确定基本的生化和生理机制的调节脑血流量（CBF）和能量代谢在休息和响应功能激活。今年完成和发表的研究表明，atp敏感的K+离子通道存在于血管平滑肌中，用于松弛肌肉，产生血管舒张，但与神经元功能激活相关的CBF增加无关。此外，今年完成和发表的其他研究已经推翻了多巴胺受体参与CBF功能激活的假设。今年完成的研究已经证实，星形胶质细胞和神经元之间存在葡萄糖代谢的区隔化。星形胶质细胞将葡萄糖代谢为乳酸，并将其输出到神经元，神经元将其氧化为二氧化碳和水。这些研究表明，神经元容易氧化葡萄糖和乳酸，但在动力学上更倾向于氧化来自细胞外空间的乳酸，而不是通过糖酵解在细胞内产生的丙酮酸/乳酸。星形胶质细胞也可以将葡萄糖和乳酸氧化为二氧化碳，但它们很少这样做，它们主要将葡萄糖代谢为乳酸。星形胶质细胞的能力有限是由于丙酮脱氢酶（PDH）活性有限。该酶主要以磷酸化失活形式存在于星形胶质细胞中，但它可以被二氯乙酸激活，我们发现二氯乙酸可以刺激星形胶质细胞氧化乳酸并减少其向神经元输出乳酸。在体内给药时，它对大鼠的总体行为没有产生明显的变化，并导致大脑葡萄糖利用的增加，这可能是由于葡萄糖的利用增加了，以补偿从星形胶质细胞进口乳酸的减少。这些研究的结论是，神经元和星形胶质细胞之间的葡萄糖代谢确实存在区隔化，但它既不是完全的，也不是必须的。

This is an omnibus project that covers a variety of studies on development, validation, refinement, and applications of methods to determine basic biochemical and physiological mechanisms underlying the regulation of cerebral blood flow (CBF) and energy metabolism at rest and in response to functional activation. Studies completed and published this year have shown that ATP-sensitive K+ ion channels, which exist in vascular smooth muscle and serve to relax the muscle producing vasodilatation, do not contribute to the increases in CBF associated with neuronal functional activation. Also, other studies completed this year and in press have disproved the hypothesis that dopamine receptors are involved in the functional activation of CBF. Studies completed this year have confirmed that there is a compartmentalization of glucose metabolism between astroglia and neurons. The astroglia metabolize glucose to lactate and export it to neurons which oxidize it to CO2 and H2O. These studies showed that neurons readily oxidize both glucose and lactate but have a kinetic preference to oxidize lactate derived from the extracellular space over pyruvate/lactate produced intracellularly by glycolysis. Astroglia also can oxidize both glucose and lactate to CO2, but they do so sparingly, and they metabolize glucose mainly to lactate. The limited ability of the astroglia is due to limited pyruvic dehydrogenase (PDH) activity. This enzyme exists in astroglia predominantly in the phosphorylated inactive form, but it can be activated by dichloroacetate, which we found can stimulate astroglia to oxidize lactate and diminish their export of lactate to neurons. When administered in vivo to rats, it produced no obvious changes in gross behavior and led to increases in cerebral glucose utilization, presumably due to increased utilization of glucose to compensate for the diminished import of lactate from the astroglia. The conclusion from these studies is that the compartmentalization of glucose metabolism between neurons and astroglia does exist, but it is neither complete nor obligatory. Studies on two strains of mutant mice with either the alpha or the beta thyroid receptor genetically altered so that they could not bind L-triiodothyronine are still in progress. Part of the results were published this year. Cerebral glucose utilization was found to be completely normal in the mice with the altered beta thyroid hormone receptor, but was markedly and diffusely depressed in the mice with the dysfunctional alpha-receptor as it is in animals made cretinism by radiothyroidectomy at birth. These results indicate that the beta thyroid hormone receptor has little if anything to do with normal brain development and that the effects of thyroid hormone on brain development are mediated by the alpha thyroid hormone receptor. Studies currently in progress are showing that although the baseline glucose utilization in cerebral structures is markedly reduced, the percent increases in their use of glucose evoked by neuronal functional activation is the same, indicating that the decreased baseline glucose utilization is due to diminished synaptic density but the remaining synapses are functionally normal.