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Oxygen and the Spark of Human Brain Evolution: Complex Interactions of Metabolism and Cortical Expansion across Development and Evolution.

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Rosas, Fernando E 
Noonan, MaryAnn P 
Mediano, Pedro AM 
Kringelbach, Morten L 


Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development-before and after birth and through maturation to adulthood-and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain-favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for neural plasticity sets the conditions for cognitive flexibility and ongoing learning, supporting complex group dynamics and intergenerational learning that in turn enabled improved nutrition to fuel the metabolic costs of further cortical expansion. Our proposed model delineates explicit mechanistic links among metabolism, molecular and cellular brain heterogeneity, and behavior, which may lead toward a clearer understanding of brain development and its disorders.


Peer reviewed: True

Funder: Ad Astra Chandaria Foundation

Funder: Carlsbergfondet; FundRef:

Funder: National Institute for Health Research; FundRef:

Funder: King’s College London; FundRef:


aerobic glycolysis, complex systems, cortical expansion, development, evolution, metabolism, oxygen, plasticity, social brain, transmodal association cortex, Humans, Oxygen, Brain, Cerebral Cortex, Longitudinal Studies, Learning, Biological Evolution

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SAGE Publications
Wellcome Trust (210920/Z/18/Z)
AIL supported by a Gates Cambridge Scholarship (OPP 1144); FER is funded by the Ad Astra Chandaria foundation; PAM is funded by the Wellcome Trust (grant no. 210920/Z/18/Z); MLK is supported by the Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing at Linacre College funded by the Pettit and Carlsberg Foundations; EAS is supported by the Canadian Institute for Advanced Research (CIFAR) (RCZB/072 RG93193) and the Stephen Erskine Fellowship (Queens’ College, Cambridge); ACV acknowledges funding supporting this work from the Medical Research Council UK Centre grant MR/ N026063/1; FET is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London.