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。去年的研究发现，在沿着神经通路的不同中继站，在功能激活过程中调节CBF的多种机制在今年发表。在功能激活过程中，血管平滑肌中的腺苷和腺苷受体参与初级突触CBF的增加，而在多突触通路的高级站，神经元一氧化氮合酶产生的一氧化氮（NO）似乎起作用。然而，腺苷和一氧化氮都不能完全解释功能激活引起的CBF增加，必须涉及其他因素。今年完成和发表的研究表明，麻醉明显抑制CBF在激活通路中含有高级突触的区域的功能激活，而在初级突触区域则没有。正在进行但几乎完成的研究表明，星形胶质细胞和神经元之间存在一种共生代谢关系，星形胶质细胞的代谢可能密切参与脑血流的调节。培养的星形胶质细胞容易将葡萄糖代谢为乳酸，但将乳酸氧化为CO2和水的能力有限；相反，它们会将其排出体外。据推测，体内的神经元可以代谢乳酸和葡萄糖，吸收乳酸并将其氧化为二氧化碳和水，以获得支持神经元尖峰活动所需的能量。二氯乙酸刺激乳酸的星形胶质氧化。体内给药后，二氯乙酸增强了功能激活引起的脑血流的增加，提示星形胶质细胞氧化代谢可能在脑血流功能激活的调节中起作用。在过去的一年中，对两种突变小鼠的研究已经完成并发表或出版。我们在敲除α -半乳糖苷酶a的fabry病小鼠模型中测量了局部CBF和葡萄糖利用（lCMRglc）。与人类疾病一样，该模型显示神经酰胺三己糖苷在整个大脑中沉积，主要在血管平滑肌和内皮细胞中。这些突变体显示lCMRglc的广泛减少，但没有预期的局部CBF的相应减少。这些结果表明，脑糖代谢的损害不是由于脑灌注不足，而是由于继发于血管病变的葡萄糖从血液转运到脑的减少。研究还对两种突变小鼠进行了研究，这两种突变小鼠的α或β甲状腺受体发生了基因改变，因此它们不能与l -三碘甲状腺原氨酸结合。在甲状腺激素受体改变的小鼠中，局部脑葡萄糖利用完全正常，但在α受体功能失调的小鼠中，局部脑葡萄糖利用像放射甲状腺切除术引起的克汀病一样弥漫性受损。这些结果表明-甲状腺激素受体与正常的大脑发育几乎没有关系，甲状腺激素对大脑发育的影响是由-甲状腺激素受体介导的。

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. Findings of the previous year that multiple mechanisms for regulation CBF during functional activation operate at different relay stations along a neural pathway were published this year. Adenosine and adenosine receptors in vascular smooth muscle are involved in increasing CBF in the primary synapses during functional activation while at higher level stations in multisynaptic pathways nitric oxide (NO)produced by neuronal nitric oxide synthase appears to play a role. Neither adenosine nor nitric oxide fully account, however, for the increases in CBF evoked by functional activation, and other factors must be involved. Studies completed and published this year have shown that anesthesia markedly suppresses functional activation of CBF in regions containing higher level synapses of the activated pathway but not in the regions of the primary synapses. Studies in progress but almost completed indicate that there is a symbiotic metabolic relationship between astroglia and neurons and that astroglial metabolism may be intimately involved in the regulation of CBF. Astroglia in culture readily metabolize glucose to lactate but show limited ability to oxidize the lactate to CO2 and water; instead they excrete it. Presumably, in vivo neurons, which can metabolize lactate as well as glucose, take up the lactate and oxidize it to CO2 and water to derive the energy needed to support spike activity in the neurons. Dichloracetate stimulates astroglial oxidation of lactate. When given in vivo dichloracetate enhances the increases in CBF evoked by functional activation suggesting that astroglial oxidative metabolism nay play a role in the regulation of CBF to functional activation. Studies on two types of mutant mice were completed and published or in press this past year. Local CBF and glucose utilization (lCMRglc) wee measured in a mouse model of Fabry’s diseases, in which the alpha-galactosidase A enzyme was knocked out. As in the human disease, this model exhibits deposits of ceramide trihexoside throughout the brain, mainly in vascular smooth muscle and endothelial cells.. These mutants showed widespread reductions in lCMRglc but without the expected corresponding reductions in local CBF. These results suggest that the impairment in cerebral glucose metabolism is not due to inadequate perfusion of the brain but to reduced transport of glucose from blood to brain secondary to the vasculopathy. Studies were also carried out in two strains of mutant mice with either the alpha or the beta thyroid receptor genetically altered so that they could not bind L-triiodothyronine. There was completely normal local cerebral glucose utilization in the mice with the altered beta thyroid hormone receptor, but in the mice with the dysfunctional alpha-receptor, local cerebral glucose utilization was diffusely impaired just as it is in cretinism induced by radiothyrodectomy. 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.