Brain-wide reconfiguration of burst firing by psilocybin reveals 5-HT2A-dependent circuit dynamics.

Authors

D Momi, Y Nahas, D Wyrick, L C Marks, L D Claar, R De Filippo, P Seyfourian, D A Pizzagalli, M Buice, T Ott, C Koch, I Rembado

Published in

bioRxiv : the preprint server for biology. Sep 07, 2026. Epub Sep 07, 2026.

Abstract

Psilocybin produces rapid and lasting therapeutic effects, yet how 5-HT2A receptor activation reshapes brain-wide circuit dynamics during acute drug administration remains poorly understood. Using simultaneous multi-region Neuropixels recordings of 46,360 single units from 35 mice, together with scalp electroencephalography (EEG), pupillometry, and locomotion monitoring, we provide a brain-wide, single-unit and field-potential characterization of psilocybin's acute effects, with pharmacological dissection using the 5-HT2A antagonist ketanserin. Psilocybin selectively reconfigured burst coding, rather than mean firing rate, across cortical, thalamic, and hippocampal circuits: burst firing decreased in hippocampal CA1-CA3 and was bidirectionally modulated in the thalamus, with the reticular nucleus bursting more and first-order geniculate nuclei bursting less. Critically, most of these burst effects were abolished by ketanserin, consistent with at least partial 5-HT2A receptor dependence. These data suggest that the psychedelic state is not simply a matter of how much neurons fire, but of how they fire, pointing to a region-specific, 5-HT2A-associated reconfiguration of burst coding that may underlie the acute phenomenology of the psilocybin experience.

PMID:
42818490
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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