NONINVASIVE STUDY OF CEREBRAL ATP METABOLISM, BIOENERGETICS AND BRAIN FUNCTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 三磷酸腺苷(ATP)主要通过氧化磷酸化和F1F0-ATPase在线粒体中形成，为驱动大脑中大多数细胞活动提供能量。这种氧化的ATP代谢在大脑的生物能量、功能和疾病中起着至关重要的作用。直接评价体内ATPase反应代谢率的唯一可能方法是体内31P MRS结合磁化转移(MT)。然而，以往对灌流心脏的研究表明，活体31P-MT法测得的表观ATP合成速率与氧化磷酸化及其变化的净速率并不耦合。相反，我们最近的工作表明，通过ATPase反应测得的脑内ATP代谢率(CMRATP)与麻醉动物和清醒人类的净氧化磷酸化速率密切相关，并且对不同的基线活动和/或脑刺激引起的脑活动变化也很敏感。这些令人信服的发现导致了我们的中心假设：在体内，31P-MT法应该适合于测量和成像CMRATP，它直接反映了ADP氧化磷酸化的净速率，从而产生了大脑中的大部分ATP分子；而这种体内方法的建立，可以为研究氧化ATP代谢在调节与脑功能和功能障碍相关的神经能量学中的核心作用提供一种宝贵的、完全无创的神经成像模式。这一假设将通过四个具体目标得到验证：1)进一步优化和改进体内31P MT测量和定量方法，以使用高场动物模型准确地测定CMRATP；2)使用我们新开发的高场体内17O MRS成像方法，在不同基线活动水平的静息脑中同时无创性地测量CMRATP和脑氧代谢速率(CMRO2)，并检查CMRATP是否对脑活动变化敏感，以及CMRATP是否与广泛脑活动生理范围下的氧化磷酸化速率相关；3)利用视觉刺激进行功能激活研究，以检查激活的视皮层中的CMRATP是否增加，以支持更高的能量需求和刺激诱发的神经元活动；4)在静息和激活条件下进行细胞外神经元记录研究，并将电生理学结果与CMRATP结果进行关联，以提供对静息和激活大脑中神经-ATP-代谢耦合关系的新见解。这项研究的意义在于两个层面：建立一种独特的神经成像模式来成像CMRATP：大脑能量的最基本和最直接的测量；以及了解氧化ATP代谢在神经能量学和神经生理学中对支持大脑功能和工作的可能作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Adenosine triphosphate (ATP), which mainly formed in mitochondria through oxidative phosphorylation and F1F0-ATPase, provides energy for driving most cellular activities in the brain. This oxidative ATP metabolism plays essential roles in brain bioenergetics, function and disease. The sole approach possible for directly assessing the metabolic rate of ATPase reaction in situ is the use of in vivo 31P MRS combined with magnetization transfer (MT). However, previous work of perfused heart suggested that the apparent ATP synthesis rate measured by in vivo 31P MT approach was not coupled with the net rate of oxidative phosphorylation and its change. In contrast, our recent work has shown that the measured cerebral metabolic rate of ATP (CMRATP) via ATPase reaction is closely matched with the net oxidative phosphorylation rate in anesthetized animals and awaked human, and it is also sensitive to the change of brain activity induced by varied baseline activity and/or brain stimulation. These compelling findings have led to our central hypothesis: In vivo 31P MT approach should be suitable for measuring and imaging CMRATP, which directly reflects the net rate of oxidative phosphorylation of ADP for producing the majority of brain ATP molecules; and establishment of this in vivo approach can provide an invaluable, completely noninvasive neuroimaging modality for studying the central roles of oxidative ATP metabolism in regulating neuroenergetics associated with brain function and dysfunction. This hypothesis will be tested by four specific aims: 1) to further optimize and improve in vivo 31P MT measurements and quantification methods for accurately determining CMRATP using an animal model at high field; 2) to conduct concurrent noninvasive measurements of CMRATP and the cerebral metabolic rate of oxygen (CMRO2) using our newly developed high-field in vivo 17O MRS imaging approach in resting brains with varied baseline activity levels, and to examine if CMRATP is sensitive to brain activity change, and if CMRATP correlates to the rate of oxidative phosphorylation under a wide physiological range of brain activity; 3) to conduct functional activation studies using visual stimulation to examine if CMRATP increases in the activated visual cortex for supporting higher energy demand and stimulus-evoked neuronal activity; 4) to conduct extracellular neuron-recording studies under resting and activated conditions, and to correlate electrophysiology results with CMRATP results for providing new insights into the neuro-ATP-metabolic coupling relationships in the resting and activated brain. The significance of this research lies in two layers: to establish a unique neuroimaging modality for imaging CMRATP: a most fundamental and direct measure of brain energy; and to understand the possible roles of oxidative ATP metabolism in neuroenergetics and neurophysiology for supporting brain function and work.