Dynamic MRI and MRS studies of focal neural activation

描述(申请人提供)：神经元活动增加与新陈代谢增加之间的联系机制尚不完全清楚。该项目的长期目标是在细胞水平上揭示大脑能量代谢与神经传递之间的耦合机制。这项应用的目的是利用一种新的技术，即活体13C动态13C同位素分析，来测量神经元和星形胶质细胞之间的脑分区代谢。将被检验的假设是：(A)用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，并在局灶性激活时增加(电活动增加)。(B)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)只有一小部分大脑产生的能量用于支持谷氨酸能神经传递。其具体目的是：(1)确定最佳的13C标记底物或底物组合，用于使用动态13C同位素分析可靠地测量体内脑内的分区代谢通量。(2)用不同的大鼠脑内麻醉剂，在不同的脑活动水平下，测量包括谷氨酸-谷氨酰胺循环在内的全脑分区代谢通量。(3)测定谷氨酰胺合成酶抑制剂蛋氨酸亚硫胺和胶质细胞TCA循环抑制剂氟乙酸酯对大鼠脑内神经元-胶质细胞代谢的药理抑制作用后的区间化代谢通量。(4)测定猫和人脑在视觉刺激过程中激活的皮质中包括谷氨酸-谷氨酰胺循环在内的区域化代谢通量。这项工作的基本原理是，它将在星形胶质细胞-神经元相互作用的背景下更好地理解神经传递，并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。这将为评估一系列大脑疾病的谷氨酸能功能打开令人兴奋的前景，在结构损伤尚不明显的阶段，怀疑谷氨酸能神经传递功能障碍。

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.