Abstract
The mammalian brain relies on neurochemistry to fulfill its functions. Yet, the complexity of the brain metabolome and its changes during diseases or aging remain poorly understood. Here, we generate a metabolome atlas of the aging wildtype mouse brain from 10 anatomical regions spanning from adolescence to old age. We combine data from three assays and structurally annotate 1,547 metabolites. Almost all metabolites significantly differ between brain regions or age groups, but not by sex. A shift in sphingolipid patterns during aging related to myelin remodeling is accompanied by large changes in other metabolic pathways. Functionally related brain regions (brain stem, cerebrum and cerebellum) are also metabolically similar. In cerebrum, metabolic correlations markedly weaken between adolescence and adulthood, whereas at old age, cross-region correlation patterns reflect decreased brain segregation. We show that metabolic changes can be mapped to existing gene and protein brain atlases. The brain metabolome atlas is publicly available (https://mouse.atlas.metabolomics.us/) and serves as a foundation dataset for future metabolomic studies.
Highlights
The mammalian brain relies on neurochemistry to fulfill its functions
After euthanasia, brains were harvested and dissected into the following 10 anatomically defined regions: cerebral cortex (CT), olfactory bulb (OB), hippocampus (HC), hypothalamus (HT), basal ganglia (BG), thalamus (TL), midbrain (MB), pons (PO), medulla (MD), and cerebellum (CB). These 640 brain samples were analyzed by combining data from three untargeted metabolomic platforms: primary metabolism by gas chromatography-time of flight mass spectrometry (GC-TOF MS) and two assays using orbital ion trap highresolution mass spectrometry (Q-Exactive HF MS/MS) by separating biogenic amines using hydrophilic interaction chromatography (HILIC) and separating complex lipids by charged surface hybrid (CSH) reversed phase (RP) liquid chromatography (LC)
Complex lipids accounted for the largest proportion of the brain metabolome due to the high endogenous contents of brain lipids ranging from phosphatidylcholines (PC), phosphatidylethanolamines (PEs), triacylglycerol (TGs), fatty acids (FAs), phosphatidylserines (PS), phosphatidylinositols (PIs), sphingomyelins (SM), ceramides (Cers) to diacylglycerols (DGs) and others
Summary
The mammalian brain relies on neurochemistry to fulfill its functions. Yet, the complexity of the brain metabolome and its changes during diseases or aging remain poorly understood. We generate a metabolome atlas of the aging wildtype mouse brain from 10 anatomical regions spanning from adolescence to old age. The brain is one of the most structurally and functionally complex organs in mammals[1,2,3,4] It is characterized by a unique morphology of anatomical regions, intricate brain network connectivity, an enormous variety of cell types, and a highly integrated molecular program during brain development and aging. The brain metabolome has been studied inadequately, either focusing on a few metabolites[12,13] or restricting study designs and data acquisition to incomplete coverage of neurochemistry and brain anatomical regions[14,15,16,17]. We created a freely accessible web tool to allow interactive exploration of the brain metabolome atlas at https://mouse.atlas.metabolomics.us/
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