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

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Title: A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex
Authors: Luppi, AI
Girn, M
Rosas, FE
Timmermann, C
Roseman, L
Erritzoe, D
Nutt, DJ
Stamatakis, EA
Spreng, RN
Xing, L
Huttner, WB
Carhart-Harris, RL
Item Type: Journal Article
Abstract: Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signaling 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 signaling 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 signaling plays a major role in both human cortical expansion and functioning. Due 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.
Issue Date: Jan-2024
Date of Acceptance: 18-Aug-2023
URI: http://hdl.handle.net/10044/1/106833
DOI: 10.1093/brain/awad311
ISSN: 0006-8950
Publisher: Oxford University Press
Start Page: 56
End Page: 80
Journal / Book Title: Brain: a journal of neurology
Volume: 147
Issue: 1
Copyright Statement: Copyright © 2023 Oxford University Press. This is a pre-copy-editing, author-produced version of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version Andrea I Luppi, Manesh Girn, Fernando E Rosas, Christopher Timmermann, Leor Roseman, David Erritzoe, David J Nutt, Emmanuel A Stamatakis, R Nathan Spreng, Lei Xing, Wieland B Huttner, Robin L Carhart-Harris, A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex, Brain, 2023;, awad311, is available online at: https://doi.org/10.1093/brain/awad311
Publication Status: Published
Conference Place: England
Article Number: awad311
Online Publication Date: 2023-09-13
Appears in Collections:Faculty of Medicine
Department of Brain Sciences