Mapping energy metabolism gene expression in the human brain
Poster No:
1734
Submission Type:
Abstract Submission
Authors:
Moohebat Pourmajidian1, Justine Hansen2, Golia Shafiei3, Bratislav Misic4, Alain Dagher2
Institutions:
1McGill University, Montréal, QC, 2McGill University, Montreal, QC, 3University of Pennsylvania, Philadelphia, PA, 4Montreal Neurological Institute, Montreal, Quebec
First Author:
Co-Author(s):
Introduction:
The brain relies on substantial energy to maintain its complex signalling functions and housekeeping processes. The brain has minimal energy reserve, neurons therefore rely on constant nutrient supply and energy production tightly coupled to synaptic and spiking activity. Energy metabolism refers to pathways and processes involved in the breakdown of nutrient molecules to produce adenosine triphosphate. Beyond energy production, energy metabolic pathways (e.g., the pentose phosphate pathway) provide cellular building blocks such as nucleotides, amino acids, and fatty acids required for cellular growth and repair. Despite extensive research on glucose and oxygen uptake in the brain, the downstream energy metabolism pathways responsible for nutrient use and their correspondence to cortical organization remains largely unexplored. In this study, we aim to provide further insight into the energy metabolism profile of the human brain.
Methods:
We produce maps of five key energy metabolism processes including: glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation and lactate metabolism, using curated pathway-specific gene sets retrieved from Gene Ontology and Reactome databases. Briefly, gene expression data were retrieved from the Allen Human Brain Atlas using the abagen package (Markello et al., 2021) and parcellated into 400 cortical regions (Schaefer et. al, 2018). Pathway-specific gene expression matrices were then averaged across genes to create a single mean expression map for each pathway. We then study how energy maps relate to the microstructural and functional properties in the human brain, using a set of annotation including: intrinsic functional (Yeo et al., 2011), cytoarchitectonics (Triarhou, 2007) and sensory-fugal network classes (Mesulam 1998), PET metabolic maps of glucose and oxygen uptake and cerebral blood flow, MEG maps from the neuromaps package (Markello et al., 2022), cell type expression maps (Seidlitz et al., 2020) and measures of functional and structural connectivity (Vos De Wael et al., 2018). Finally, we study the expression trajectory of these energy pathways across the lifespan using the BrainSpan RNA-sequencing and microarray datasets. Analysis was repeated across different parcellations, and spatial null models were employed to test the reliability and statistical significance of the results.
Results:
We show that energy pathways exhibit heterogeneous expression across the cortex, with glycolysis and oxidative phosphorylation pathways exhibiting greater expression in the motor cortices and lower expression in the visual cortex. The pentose phosphate pathway shows higher expression in the idiotypic regions including the somato-sensory and visual cortices, suggesting higher biosynthesis demand in these regions involved in sensory encoding. Using lifespan brain regional transcriptome, we show that energy pathways exhibit diverse trajectories from the fetal stage to adulthood, that closely track the developmental milestones. Notably, the main ATP-producing pathways including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation peak in childhood, while the pentose phosphate pathway declines following the early stages of brain development and throughout the later stages of life.
Conclusions:
Here, we employ neuroimaging transcriptomic techniques, to demonstrate that cortical regions possess distinct energy profiles, with the main energy-producing pathways and anabolic pathways such as the pentose phosphate pathway exhibiting a general dichotomy in the unimodal cortices. Finally, we show that energy metabolism pathways have unique expression trajectories across the lifespan that reflect nutrient availability and biosynthesis needs. Collectively, these results highlight the complexity and the heterogeneity of the metabolic systems in the brain.
Genetics:
Transcriptomics
Lifespan Development:
Early life, Adolescence, Aging
Modeling and Analysis Methods:
Multivariate Approaches
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping 1
Physiology, Metabolism and Neurotransmission:
Cerebral Metabolism and Hemodynamics 2
Keywords:
Cortex
Development
Other - energy metabolism, neuroimaging trasncriptomics
1|2Indicates the priority used for review
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Markello, R. D., (2022). neuromaps: Structural and functional interpretation of brain maps. Nature Methods, 19(11), 1472–1479. https://doi.org/10.1038/s41592-022-01625-w
Mesulam, M. (1998). From sensation to cognition. Brain, 121(6):1013–1052. https://doi.org/10.1093/brain/121.6.1013
Schaefer, A., (2018). Local-Global Parcellation of the Human Cerebral Cortex from Intrinsic Functional Connectivity MRI. Cerebral Cortex, 28(9), 3095–3114. https://doi.org/10.1093/cercor/bhx179
Seidlitz, J., (2020). Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-17051-5
Thomas Yeo, (2011). The organization of the human cerebral cortex estimated by intrinsic functional connectivity. Journal of Neurophysiology, 106(3), 1125–1165. https://doi.org/10.1152/jn.00338.2011
Triarhou, L. C. (2007). The Economo-Koskinas atlas revisited: Cytoarchitectonics and functional context. In Stereotactic and Functional Neurosurgery (Vol. 85, Issue 5, pp. 195–203). https://doi.org/10.1159/000103258
Vos De Wael, R., (2018). Anatomical and microstructural determinants of hippocampal subfield functional connectome embedding. Proceedings of the National Academy of Sciences, 115(40), 10154–10159. https://doi.org/10.1073/pnas.1803667115