MRS Studies of Neurotransmitter Cycling in Human Brain

描述(申请人提供)：在过去的十年里，人们对星形胶质新陈代谢如何支持神经元功能的兴趣重新抬头。磁共振波谱(MRS)结合稳定的~(13)C标记前体是唯一可用于无创研究人类神经元/神经胶质代谢关系的方法。在我们之前的资金周期中，我们使用13C MRS表明，神经元/神经胶质细胞谷氨酸/谷氨酰胺循环在人脑皮质中高度活跃，是神经元谷氨酸补充和星形胶质细胞谷氨酰胺合成的主要途径。在这项研究的过程中，我们开发了一种使用2-13C醋酸酯的人类研究的新标记策略。醋酸盐作为大脑燃料是独特的，因为它几乎只在星形胶质细胞中代谢，这一特性使其成为研究神经元/神经胶质神经递质循环的理想材料。这笔赠款的主要目标是在4T进一步发展2-13C乙酸酯/MRS方法，然后用它来回答关于神经元/神经胶质神经递质周期在正常大脑功能中的作用的几个关键问题。我们的具体目标是在人类大脑皮层进行：(1)表征醋酸盐的运输和代谢，以便通过醋酸盐示踪剂研究确定绝对速率；(2)通过以更高的空间分辨率测量神经元/胶质谷氨酸/谷氨酰胺循环及其与神经元和胶质葡萄糖氧化的偶联，研究胶质细胞在支持兴奋功能中的作用；(3)通过测量GABA/谷氨酰胺循环和GABA能神经元葡萄糖氧化，研究胶质细胞在支持抑制功能中的作用；以及(4)评估星形胶质细胞谷氨酸氧化对维持正常神经元功能的重要性。此外，我们将通过与使用1-13C葡萄糖示踪剂获得的结果进行比较，以及通过评估代谢率的测试-重新测试稳定性来验证这些测量。虽然没有提出患者研究，但我们的目标是为这些研究提供有效的方法学和规范性价值，用于未来对发育、衰老和疾病中神经元-神经胶质神经递质周期的研究。

DESCRIPTION (provided by applicant): The last decade has seen a renaissance of interest in how astroglial metabolism supports neuronal function. Magnetic Resonance Spectroscopy (MRS) in combination with stable 13C labeled precursors is the only method which may be used for studying neuronal/glial metabolic relationships non invasively in humans. In our previous funding cycle we used 13C MRS to show that the neuronal/glial glutamate/glutamine cycle is highly active in human cerebral cortex, and is the major pathway of both neuronal glutamate repletion and astroglial glutamine synthesis. In the course of this research we developed a novel labeling strategy for human studies using 2-13C acetate. Acetate is unique as a brain fuel because it is almost exclusively metabolized in astroglial cells, a property which makes it ideal for studying neuronal/glial neurotransmitter cycles. The primary goals of this grant are to further develop the 2-13C acetate/MRS method at 4T, and then use it to answer several pivotal questions on the role of neuronal/glial neurotransmitter cycles in normal brain function. Our specific aims are in human cerebral cortex to (1) characterize acetate transport and metabolism to allow absolute rates to be determined from acetate tracer studies, (2) study the role of glia in supporting excitatory function by measuring with much higher spatial resolution the neuronal/glial glutamate/glutamine cycle and its coupling to neuronal and glial glucose oxidation (3) study the role of glia in supporting inhibitory function by measuring the GABA/glutamine cycle and GABAergic neuron glucose oxidation and (4) assess the importance of astroglial glutamate oxidation for maintaining proper neuronal function. In addition we will validate these measurements both through comparison with results obtained using a 1-13C glucose tracer, and by assessing test-retest stability of metabolic rates. Although no patient studies are proposed, our goal is for these studies to provide validated methodology and normative values to be used in future studies of neuronal-glial neurotransmitter cycles in development, aging, and disease.