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A molecular and cellular perspective on human brain evolution and tempo

Abstract

The evolution of the modern human brain was accompanied by distinct molecular and cellular specializations, which underpin our diverse cognitive abilities but also increase our susceptibility to neurological diseases. These features, some specific to humans and others shared with related species, manifest during different stages of brain development. In this multi-stage process, neural stem cells proliferate to produce a large and diverse progenitor pool, giving rise to excitatory or inhibitory neurons that integrate into circuits during further maturation. This process unfolds over varying time scales across species and has progressively become slower in the human lineage, with differences in tempo correlating with differences in brain size, cell number and diversity, and connectivity. Here we introduce the terms ‘bradychrony’ and ‘tachycrony’ to describe slowed and accelerated developmental tempos, respectively. We review how recent technical advances across disciplines, including advanced engineering of in vitro models, functional comparative genetics and high-throughput single-cell profiling, are leading to a deeper understanding of how specializations of the human brain arise during bradychronic neurodevelopment. Emerging insights point to a central role for genetics, gene-regulatory networks, cellular innovations and developmental tempo, which together contribute to the establishment of human specializations during various stages of neurodevelopment and at different points in evolution.

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Fig. 1: A comparative overview of evolutionary specializations of the human brain.
Fig. 2: Neurodevelopmental tempo has become progressively slower, or bradychronic, in human evolution.
Fig. 3: Neurodevelopment in human and non-human primates.

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Acknowledgements

The authors thank their colleagues for inspiring scientific discussions. This work was supported by the Netherlands Organisation for Scientific Research (NWO-Rubicon, 019.211EN.032ß) and an European Molecular Biology Organisation non-stipendiary postdoctoral fellowship (EMBO, ALTF 845–2021) to F.W.L.; an Klingenstein-Simons fellowship, a Simons Foundation BTI award, and an NIH BRAIN Initiative grant (UM1MH130981) to F.M.K.; the Gladstone Institutes, Chan Zuckerberg Biohub San Fransisco and the NIMH (U01-MH116438) to K.S.P.; and the Medical Research Council (MC_UP_1201/9) and the European Research Council (ERC-STG, 757710) to M.A.L.

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All authors contributed to writing and reviewing the manuscript. Specifically, F.W.L. and M.A.L. planned and outlined the manuscript, F.W.L. drafted the manuscript and figures, F.M.K. contributed to sections on cellular diversity, K.S.P. contributed to sections on evolutionary genetics and mechanisms, M.A.L. contributed to sections on human-specific brain evolution and nomenclature, and all authors contributed to editing and finalizing the manuscript.

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Correspondence to Feline W. Lindhout or Madeline A. Lancaster.

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Lindhout, F.W., Krienen, F.M., Pollard, K.S. et al. A molecular and cellular perspective on human brain evolution and tempo. Nature 630, 596–608 (2024). https://doi.org/10.1038/s41586-024-07521-x

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