Dynamic MRI and MRS studies of focal neural activation

描述（由申请人提供）：将神经元活动增加与代谢增加联系起来的机制尚未完全了解。该项目的长期目标是在细胞水平上揭示脑能量代谢与神经传递的耦合机制。本应用程序的目的是测量神经元和星形胶质细胞之间的区隔脑代谢，使用一种新的新兴技术，即体内13C动态13C同位素分析。要测试的假设是：(a) 13C核磁共振测量的谷氨酸-谷氨酰胺循环反映了谷氨酸能神经传递，并且在局灶激活（电活动增加）期间增加。(b)在激活过程中，谷氨酸-谷氨酰胺循环的变化伴随着其他代谢通量的相应变化，如神经元和神经胶质葡萄糖氧化代谢、苹果酸-天冬氨酸穿梭和丙酮酸羧化。(c)只有一小部分的脑能生产是用来支持谷氨酸能神经传递。具体目的是：(1)利用动态13C同位素分析确定最佳的13C标记底物或底物组合，以可靠地测量脑内区隔代谢通量。(2)用不同的麻醉剂测量大鼠脑在不同的脑活动水平下全脑的区隔化代谢通量，包括谷氨酸-谷氨酰胺循环。(3)测定甲硫氨酸亚砜胺（谷氨酰胺合成酶抑制剂）和氟乙酸酯（胶质TCA循环抑制剂）对大鼠脑内神经元-胶质代谢的药理抑制作用后的区隔代谢通量。(4)测定猫和人脑视觉刺激时激活皮层的区隔化代谢通量，包括谷氨酸-谷氨酰胺循环。这项工作的基本原理是，它将导致在星形细胞-神经元相互作用的背景下更好地理解神经传递，它将验证在人脑中非侵入性测量谷氨酸能神经传递的可能性。这将为评估谷氨酸能在广泛的脑部疾病中的功能开辟令人兴奋的前景，其中怀疑谷氨酸能神经传递功能障碍，在结构病变尚未明显的阶段。

DESCRIPTION (provided by applicant): The mechanisms that link increased neuronal activity to increased metabolism are not fully understood. The LONG-TERM GOAL of this project is to uncover the mechanisms that couple brain energy metabolism to neurotransmission at the cellular level. The OBJECTIVE of this application is to measure compartmentalized brain metabolism between neurons and astrocytes, using a new emerging technique, namely in vivo 13C dynamic 13C isotopomer analysis. The HYPOTHESES to be tested are: (a) that the glutamate-glutamine cycle as measured by 13C NMR reflects glutamatergic neurotransmission and is increased during focal activation (increased electrical activity). (b) that changes in the glutamate-glutamine cycle are accompanied by matched changes in other metabolic fluxes, such as neuronal and glial glucose oxidative metabolism, malate-aspartate shuttle and pyruvate carboxylation, during activation. (c) that only a fraction of brain energy production is to used to support glutamatergic neurotransmission. The SPECIFIC AIMS are: (1) To determine the optimal 13C-labeled substrate or combination of substrates for reliable measurement of compartmentalized metabolic fluxes in the brain in vivo using dynamic 13C isotopomer analysis. (2) To measure compartmentalized metabolic fluxes, including the glutamate-glutamine cycle, in the whole brain at various levels of brain activity using different anesthetics in rat brain. (3) To measure compartmentalized metabolic fluxes following pharmacological inhibition of neuronal-glial metabolism using methionine sulfoximine (inhibitor of glutamine synthase) and fluoroacetate (inhibitor of glial TCA cycle) in rat brain. (4) To measure compartmentalized metabolic fluxes, including the glutamate-glutamine cycle, in activated cortex during visual stimulation in cat and human brain. The RATIONALE for this work is that it will lead to a better understanding of neurotransmission in the context of astrocyte-neuron interactions, and it will validate the possibility of measuring glutamatergic neurotransmission non-invasively in the human brain. This will open exciting prospects for assessing glutamatergic function in a wide range of brain disorders in which a dysfunction of glutamatergic neurotransmission is suspected, at a stage where structural lesions are not yet apparent.