Dynamic MRI and MRS studies of focal neural activation

描述（由申请人提供）：尚未完全了解将神经元活性增加与代谢增加联系起来的机制。该项目的长期目标是揭示在细胞水平上将大脑能量代谢与神经传递耦合的机制。本申请的目的是使用一种新兴技术，即体内13 C动态13 C同位素分析，测量神经元和星形胶质细胞之间的区室化脑代谢。待检验的假设为：（a）通过13 C NMR测量的谷氨酸-谷氨酰胺循环反映了谷氨酸能神经传递，并且在局灶性激活期间增加（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匹配变化，例如在激活期间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)只有一小部分的大脑能量产生是用来支持多巴胺能神经传递的。具体目标是：（1）确定最佳的13 C标记底物或底物组合，用于使用动态13 C同位素分析在体内可靠地测量脑中的区室化代谢通量。(2)在大鼠脑中使用不同的麻醉剂在不同脑活动水平下测量全脑中的区室化代谢通量，包括谷氨酸-谷氨酰胺循环。(3)在大鼠脑中，使用蛋氨酸亚砜亚胺（谷氨酰胺合成酶抑制剂）和氟乙酸盐（神经胶质TCA循环抑制剂）对神经元-神经胶质代谢进行药理学抑制后，测定区室化代谢通量。(4)测量猫和人脑在视觉刺激期间激活皮层中的区室化代谢通量，包括谷氨酸-谷氨酰胺循环。这项工作的理由是，它将使人们更好地了解星形胶质细胞-神经元相互作用背景下的神经传递，并将验证非侵入性测量人脑中谷氨酸能神经传递的可能性。这将打开令人兴奋的前景，在广泛的大脑疾病，其中的神经传递功能障碍的神经递质被怀疑，在一个阶段，结构性病变还不明显的评估神经递质功能。

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.