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.
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