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

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

doi:10.64898/2026.08.14.744865

bioRxiv · 10.64898/2026.08.14.744865

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

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

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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.

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Momi, D., Nahas, Y., Wyrick, D., Marks, L. C., Claar, L. D., De Filippo, R., Seyfourian, P., Pizzagalli, D. A., Buice, M., Ott, T., Koch, C., Rembado, I.. 2026-08-22. Brain-wide reconfiguration of burst firing by psilocybin reveals 5-HT2A-dependent circuit dynamics. https://doi.org/10.64898/2026.08.14.744865

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