TY - JOUR
T1 - Association of aerobic glycolysis with the structural connectome reveals a benefit-risk balancing mechanism in the human brain
AU - Chen, Yuhan
AU - Lin, Qixiang
AU - Liao, Xuhong
AU - Zhou, Changsong
AU - He, Yong
N1 - Funding Information:
We thank Prof. Marcus Raichle for generously sharing the PET data and for his invaluable suggestions, and Drs. Russ Hornbeck and Lars Couture for their help in the PET data analysis, Dr. Xindi Wang for his help in statistical analysis, Dr. Xiaochen Sun for her help in mediation analysis, and Drs. Mingrui Xia, Tengda Zhao, and Dingna Duan for helpful discussion. This work was supported by the Natural Science Foundation of China (Grants 81620108016, 81601560, 82021004, 31830034, 11328501, 11275027, 11975194, and 81971690), National Key Research and Development Project (Grant 2018YFA0701402), the Changjiang Scholar Professorship Award (Grant T2015027), the Hong Kong Research Grant Council (Grants HKBU12302914 and HKBU12200217), Hong Kong Baptist University (HKBU) Faculty Research Grant (FRG2/17-18/011), and the HKBU Research Committee Interdisciplinary Research Clusters Matching Scheme (IRCMs/18-19/SCI01).
Funding Information:
ACKNOWLEDGMENTS. We thank Prof. Marcus Raichle for generously sharing the PET data and for his invaluable suggestions, and Drs. Russ Hornbeck and Lars Couture for their help in the PET data analysis, Dr. Xindi Wang for his help in statistical analysis, Dr. Xiaochen Sun for her help in mediation analysis, and Drs. Mingrui Xia, Tengda Zhao, and Dingna Duan for helpful discussion. This work was supported by the Natural Science Foundation of China (Grants 81620108016, 81601560, 82021004, 31830034, 11328501, 11275027, 11975194, and 81971690), National Key Research and Development Project (Grant 2018YFA0701402), the Changjiang Scholar Professorship Award (Grant T2015027), the Hong Kong Research Grant Council (Grants HKBU12302914 and HKBU12200217), Hong Kong Baptist University (HKBU) Faculty Research Grant (FRG2/17-18/011), and the HKBU Research Committee Interdisciplinary Research Clusters Matching Scheme (IRCMs/18-19/SCI01).
PY - 2021/1/5
Y1 - 2021/1/5
N2 - Aerobic glycolysis (AG), that is, the nonoxidative metabolism of glucose, contributes significantly to anabolic pathways, rapid energy generation, task-induced activity, and neuroprotection; yet high AG is also associated with pathological hallmarks such as amyloid-β deposition. An important yet unresolved question is whether and how the metabolic benefits and risks of brain AG is structurally shaped by connectome wiring. Using positron emission tomography and magnetic resonance imaging techniques as well as computational models, we investigate the relationship between brain AG and the macroscopic connectome. Specifically, we propose a weighted regional distance-dependent model to estimate the total axonal projection length of a brain node. This model has been validated in a macaque connectome derived from tract-tracing data and shows a high correspondence between experimental and estimated axonal lengths. When applying this model to the human connectome, we find significant associations between the estimated total axonal projection length and AG across brain nodes, with higher levels primarily located in the default- mode and prefrontal regions. Moreover, brain AG significantly mediates the relationship between the structural and functional connectomes. Using a wiring optimization model, we find that the estimated total axonal projection length in these high-AG regions exhibits a high extent of wiring optimization. If these high- AG regions are randomly rewired, their total axonal length and vulnerability risk would substantially increase. Together, our results suggest that high-AG regions have expensive but still optimized wiring cost to fulfill metabolic requirements and simultaneously reduce vulnerability risk, thus revealing a benefit-risk balancing mechanism in the human brain.
AB - Aerobic glycolysis (AG), that is, the nonoxidative metabolism of glucose, contributes significantly to anabolic pathways, rapid energy generation, task-induced activity, and neuroprotection; yet high AG is also associated with pathological hallmarks such as amyloid-β deposition. An important yet unresolved question is whether and how the metabolic benefits and risks of brain AG is structurally shaped by connectome wiring. Using positron emission tomography and magnetic resonance imaging techniques as well as computational models, we investigate the relationship between brain AG and the macroscopic connectome. Specifically, we propose a weighted regional distance-dependent model to estimate the total axonal projection length of a brain node. This model has been validated in a macaque connectome derived from tract-tracing data and shows a high correspondence between experimental and estimated axonal lengths. When applying this model to the human connectome, we find significant associations between the estimated total axonal projection length and AG across brain nodes, with higher levels primarily located in the default- mode and prefrontal regions. Moreover, brain AG significantly mediates the relationship between the structural and functional connectomes. Using a wiring optimization model, we find that the estimated total axonal projection length in these high-AG regions exhibits a high extent of wiring optimization. If these high- AG regions are randomly rewired, their total axonal length and vulnerability risk would substantially increase. Together, our results suggest that high-AG regions have expensive but still optimized wiring cost to fulfill metabolic requirements and simultaneously reduce vulnerability risk, thus revealing a benefit-risk balancing mechanism in the human brain.
KW - Computational models
KW - Connectomics
KW - Default mode
KW - Metabolism
KW - Neuroimaging
UR - http://www.scopus.com/inward/record.url?scp=85098202286&partnerID=8YFLogxK
U2 - 10.1073/pnas.2013232118
DO - 10.1073/pnas.2013232118
M3 - Article
C2 - 33443160
AN - SCOPUS:85098202286
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
M1 - e2013232118
ER -