How Serotonin's 5‑HT 2A Receptor Shaped the Human Brain

Описание: This 7‑min micro‑lecture explores the evolutionary, developmental, and functional importance of the serotonin 2A receptor (5‑HT2AR) in the human brain. We will use Luppi et al.’s 2024 publication "A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex" as our guide (full citation below).

The lecture examines how 5‑HT2ARs are densely concentrated in the **transmodal cortex**, the apex of the brain’s processing hierarchy and the region most associated with abstract thought, self‑reflection, and complex cognition. Evidence suggests that during early development, 5‑HT2AR signaling stimulates the proliferation of neural progenitor cells, contributing to the dramatic cortical expansion that distinguishes the human brain from that of other species.

Beyond development, 5‑HT2AR activity enhances **functional flexibility**, **neuroplasticity**, and **context‑sensitive learning**, enabling the brain to adapt to environmental stress and high‑level cognitive demands. The authors also highlight how psychedelic compounds engage this system to temporarily relax rigid neural patterns, potentially supporting psychological transformation and therapeutic change.

Overall, the text positions the 5‑HT2AR system as a key driver of human‑specific cognition and a promising target for future mental‑health interventions. This micro‑lecture distills these insights into a clear overview of how a single receptor type may have helped shape both the structure and the capabilities of the human mind.

SCIENTIFIC ABSTRACT:
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.

SOURCE:
Luppi, A. I., Girn, M., Rosas, F. E., Timmermann, C., Roseman, L., Erritzoe, D., ... & Carhart-Harris, R. L. (2024). A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex. Brain, 147(1), 56–80.
PDF URL: https://escholarship.org/uc/item/3nb4...

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