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A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex

journal contribution
posted on 2024-04-03, 12:53 authored by Andrea I Luppi, Manesh Girn, Fernando Ernesto Rosas De AndracaFernando Ernesto Rosas De Andraca, Christopher Timmermann, Leor Roseman, David Erritzoe, David J Nutt, Emmanuel A Stamatakis, R Nathan Spreng, Lei Xing, Wieland B Huttner, Robin L Carhart-Harris
Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy—where it plays a central role in the integrative processes underpinning complex, human-defining cognition—the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation—a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Brain

ISSN

0006-8950

Publisher

Oxford University Press (OUP)

Issue

1

Volume

147

Page range

56-80

Department affiliated with

  • Informatics Publications

Institution

University of Sussex

Full text available

  • Yes

Peer reviewed?

  • Yes