Regional Cerebral Circulation And Metabolism

这是一个综合性项目，涵盖了各种方法的开发、验证、改进和应用，以确定在静息和功能激活时调节脑血流(CBF)和能量代谢的基本生化和生理机制。今年完成并发表的研究表明，存在于血管平滑肌中、用于放松产生血管扩张的肌肉的ATP敏感的K+离子通道，并不有助于与神经功能激活相关的CBF的增加。此外，今年完成的其他研究和出版中的其他研究也驳斥了多巴胺受体参与脑血流功能激活的假设。今年完成的研究证实，星形胶质细胞和神经元之间存在葡萄糖代谢的区隔。星形胶质细胞将葡萄糖代谢成乳酸，并将其输出到神经元，神经元将其氧化成二氧化碳和水。这些研究表明，神经元容易氧化葡萄糖和乳酸，但比起细胞内糖酵解产生的丙酮酸/乳酸，神经元更倾向于氧化来自细胞外空间的乳酸。星形胶质细胞也可以将葡萄糖和乳酸氧化成二氧化碳，但它们这样做很少，而且它们主要将葡萄糖代谢成乳酸。星形胶质细胞的功能受限是由于丙酮酸脱氢酶(PDH)活性有限。这种酶主要以磷酸化的非活性形式存在于星形胶质细胞中，但它可以被二氯乙酸酯激活，我们发现二氯乙酸酯可以刺激星形胶质细胞氧化乳酸，减少其向神经元的乳酸输出。在大鼠体内给药时，大体行为没有明显变化，并导致大脑葡萄糖利用率增加，这可能是由于葡萄糖利用率增加，以弥补从星形胶质细胞输入乳酸的减少。这些研究的结论是，神经元和星形胶质细胞之间确实存在葡萄糖代谢的区隔，但既不是完全的，也不是强制性的。 对两种突变小鼠的研究仍在进行中，这些突变小鼠的α或β甲状腺受体基因发生了改变，使它们不能与L-三碘甲状腺原氨酸结合。部分研究结果已于今年发表。在β-甲状腺激素受体改变的小鼠中，大脑对葡萄糖的利用完全正常，但在α-受体功能障碍的小鼠中，大脑葡萄糖利用明显而广泛地受到抑制，就像出生时通过放射甲状旁腺切除造成克汀病的动物一样。这些结果表明，β-甲状腺激素受体与正常大脑发育几乎没有关系，而且甲状腺激素对大脑发育的影响是通过α-甲状腺激素受体介导的。目前正在进行的研究表明，尽管大脑结构中的基线葡萄糖利用率显著下降，但神经元功能激活引起的葡萄糖利用率增加的百分比是相同的，这表明基线葡萄糖利用率下降是由于突触密度降低，但其余突触功能正常。

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.