Regional Cerebral Circulation And Metabolism

区域脑循环和代谢

• 批准号: 6503230
• 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/6503230
• 关键词: antipyrine; brain circulation; brain metabolism; deoxyglucose; glucose metabolism; laboratory mouse; magnetic resonance imaging; method development; nitric oxide; positron emission tomography; purinergic receptor; radiotracer

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.

这是一个综合项目，涵盖了各种方法的开发、验证、完善和应用研究，以确定静息状态下脑血流 (CBF) 和能量代谢调节以及对功能激活的反应的基本生化和生理机制。去年的研究结果今年发表，即功能激活过程中调节 CBF 的多种机制在神经通路的不同中继站运作。血管平滑肌中的腺苷和腺苷受体参与功能激活期间初级突触中 CBF 的增加，而在多突触通路的较高水平位置，神经元一氧化氮合酶产生的一氧化氮 (NO) 似乎发挥了作用。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，并且必须涉及其他因素。今年完成并发表的研究表明，麻醉显着抑制包含激活途径的高级突触区域的 CBF 功能激活，但不抑制初级突触区域。正在进行但即将完成的研究表明星形胶质细胞和神经元之间存在共生代谢关系，并且星形胶质细胞代谢可能密切参与CBF的调节。培养中的星形胶质细胞很容易将葡萄糖代谢为乳酸，但将乳酸氧化为二氧化碳和水的能力有限；相反，它们会排泄它。据推测，体内神经元可以代谢乳酸和葡萄糖，吸收乳酸并将其氧化成二氧化碳和水，以获得支持神经元尖峰活动所需的能量。二氯乙酸盐刺激星形胶质细胞乳酸的氧化。当体内给予二氯乙酸时，会增强功能激活引起的 CBF 增加，表明星形胶质细胞氧化代谢可能在 CBF 功能激活的调节中发挥作用。 对两种突变小鼠的研究已于去年完成并发表或出版。我们在法布里病小鼠模型中测量了局部 CBF 和葡萄糖利用率 (lCMRglc)，其中 α-半乳糖苷酶 A 酶被敲除。与人类疾病一样，该模型显示神经酰胺三己糖苷沉积在整个大脑中，主要是在血管平滑肌和内皮细胞中。这些突变体显示 lCMRglc 广泛减少，但局部 CBF 没有预期的相应减少。这些结果表明，脑葡萄糖代谢受损并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到脑的转运减少。还在两种突变小鼠中进行了研究，这些突变小鼠的 α 或 β 甲状腺受体经过基因改变，因此它们无法结合 L-三碘甲状腺原氨酸。在β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受体功能障碍的小鼠中，局部脑葡萄糖利用广泛受损，就像放射甲状腺切除术引起的克汀病一样。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，甲状腺激素对大脑发育的影响是由 α 甲状腺激素受体介导的。