bioRxiv : the preprint server for biologyOct 1, 2026

Psilocybin changes brain-wide burst firing patterns through 5-HT2A receptor activity

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 2, 2026

Abstract

Psilocybin administration led to a reconfiguration of burst coding across brain circuits in 35 mice.

Burst firing decreased in the hippocampal CA1-CA3 regions during psilocybin administration.
Thalamic burst firing was modulated in opposing directions, with increased activity in the reticular nucleus and decreased in the first-order geniculate nuclei.
The effects on burst firing were largely eliminated by the 5-HT2A antagonist ketanserin, indicating a potential role of these receptors.
Psilocybin's impact on brain activity suggests that the nature of neuronal firing, rather than just the amount, is crucial in understanding its acute effects.

Simplified

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.