Computational Mapping of Cerebral Metabolism During Development - PROJECT SUMMARY Understanding the timing and regulation of metabolism during development is crucial for identifying the biochemical pathways that drive brain growth. The importance of metabolism during brain development is evidenced for example by changes in mitochondrial activity, which, when disrupted, result in neurological deficits at specific age ranges. Despite this evidence, the metabolic pathways that predominate during key stages of development remain largely unknown. For the past two decades, metabolic modeling based on 13C isotopic tracing has been successfully used to quantify the activity of metabolic pathways in the brain, yet these efforts have mostly focused on the mature brain, leaving critical gaps in our understanding of metabolism during development. This project seeks to fill these gaps by tracking, quantifying, and localizing key metabolic pathways that regulate brain growth. Given its fundamental role in energy production and biosynthesis, we will focus in this project on central carbon metabolism, a network of metabolic pathways that spans from glucose uptake to its oxidation in the Krebs cycle. Preliminary data from the wildtype mouse brain indicate that glucose is primarily metabolized through glycolysis until postnatal day 15 (P15), after which oxidative metabolism becomes dominant. Additionally, during the first 10 postnatal days, the propionate-to-succinyl-CoA pathway serves as a major biosynthetic hub, transitioning to pyruvate carboxylation thereafter. Based on these findings, we hypothesize that there are two critical metabolic switches during mouse brain development: (1) a shift from glycolytic to oxidative metabolism and (2) a biosynthetic switch from the propionate-to-succinyl-CoA pathway to pyruvate carboxylation. To test this hypothesis, we propose three specific aims: (1) to determine the onset and duration of these metabolic transitions in the developing mouse brain, (2) to quantify the rates at which metabolic transitions occur, and (3) to localize the cell types where these pathways operate. This project is significant because it will pinpoint critical periods during brain development when metabolism undergoes pivotal changes, representing potential windows of vulnerability that could predispose to neurodevelopmental disorders. This proposal is innovative in its combination of the latest advancements in mass spectrometry analysis of 13C enriched metabolites with mathematical modeling to analyze and localize metabolism in the developing brain for the first time. Our long-term goals following successful completion of this project are twofold: (1) to expand this project by analyzing metabolic pathways beyond central carbon metabolism during neurodevelopment, and (2) to apply this approach to mouse models and patients with neurometabolic diseases. The knowledge gained from this project is also expected to benefit the broader scientific community, as we aim to make this platform open source to further the understanding of the role of metabolism during neurodevelopment in both health and disease.
