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

Davide MomiiD, Yasmeen NahasiD, David G WyrickiD, Lydia C. MarksiD, Leslie D. ClaariD, Roberto De FilippoiD, Parsa SeyfourianiD, Diego A. PizzagalliiD, Michael A. BuiceiD, Torben OttiD, Christof Koch AiD, Irene RembadoiD

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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.

In-depth summary

Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (7 Sept 2026) · CC BY 4.0

In awake mice, psilocybin changed burst firing rather than mean firing rate across thalamus and hippocampus. Ketanserin pretreatment abolished most burst effects, but EEG power and firing-rate changes persisted.

The paper says earlier cellular recordings of psilocybin were mostly limited to single regions, chiefly rodent prefrontal cortex, and that none had sampled single neurons across several connected circuit nodes in awake animals during the acute phase. It adds simultaneous Neuropixels recordings across cortex, thalamus, striatum and hippocampus, with a 5-HT2A antagonist control.

Key results

  1. ShownPsilocybin shifted thalamic burst rate in opposite directions by nucleus. It rose in reticular, anterior and somatomotor relay nuclei and fell in geniculate nuclei. The three increases were abolished by ketanserin.

    Burst rate versus saline: reticular FDR p<0.001, d=0.82; anterior p<0.001, d=0.76; somatomotor p=0.006, d=0.52; geniculate p=0.049, d=-0.34. Under Ket+Psi all three increases had FDR p>0.85. · Psilocybin bidirectionally modulates burst…

  2. ShownPsilocybin lowered the proportion of bursting units in hippocampal CA1, CA2 and CA3 at 40-60 min. Ketanserin abolished the CA1 and CA3 effects. Dentate gyrus and subiculum were unchanged.

    Versus saline: CA3 FDR p<0.001, d=-1.44; CA2 p=0.031, d=-0.90; CA1 p=0.044, d=-0.82. Under Ket+Psi, CA1 p=0.575 and CA3 p=0.358. CA2 was not evaluable under Ket+Psi (2 of 8 sessions). · Psilocybin bidirectionally modulates burst…

  3. ShownBurst changes did not track mean firing rate in the regional pattern. Under psilocybin, only somatosensory layer 5 had a firing-rate decrease surviving FDR correction, and no thalamic group changed. Per unit, the reticular burst-rate increase was uncorrelated with firing-rate change under psilocybin only.

    Somatosensory layer 5 firing rate FDR p=0.022, d=-0.31; heatmaps showed sparse uncorrected reductions in olfactory areas and isocortex. Reticular per-unit R²=0.02 (non-significant) under psilocybin, versus 0.14 under saline and 0.28 under Ket+Psi; prefrontal layer 5 and geniculate units kept burst and rate coupled. · Burst dynamics is dissociated from firing rate…

  4. ShownKetanserin did not block several non-burst effects. EEG high-gamma and resting alpha power fell and pupil dilation occurred under Ket+Psi. Ketanserin itself suppressed firing rates broadly in regular- and fast-spiking units.

    Ket+Psi reduced regular-spiking firing rate across five major areas and lowered layer 5 rates in prefrontal (FDR p=0.022, d=-0.26) and somatosensory cortex (p=0.005, d=-0.44). EEG: n=18 psilocybin, 14 saline, 7 Ket+Psi mice. · Multiscale electrophysiological and behavioral…; Burst dynamics is dissociated from firing rate…; Psilocybin suppresses cortical high-gamma and…; Figure legends

  5. SuggestedIn deep prefrontal layers, psilocybin held burst fraction near baseline while it fell under saline. This was a nominal trend that did not survive multiple-comparison correction and was absent under Ket+Psi.

    Layer 5 uncorrected p=0.032, d=0.24 (FDR p=0.177); layer 6 uncorrected p=0.012, d=0.35 (FDR p=0.130). Ket+Psi uncorrected p>0.31. · Psilocybin bidirectionally modulates burst…; DISCUSSION

Methods, data and reproducibility

Head-fixed mice received two intraperitoneal injections (saline/saline, saline/psilocybin 1 mg/kg, or ketanserin 1 mg/kg then psilocybin) during Neuropixels, EEG, pupil and locomotion recording. Burst metrics and firing rate during rest were compared with saline using a hierarchical bootstrap with FDR correction.

  • Neuropixels single units (38,429 regular-spiking, 7,931 fast-spiking) across cortex, thalamus, striatum and hippocampus; 22 psilocybin, 17 saline, 8 Ket+Psi sessions · mouse (C57BL/6J) · n = 46,360 units; 47 sessions; 35 mice
  • 30-channel scalp EEG spectral analysis · mouse (C57BL/6J) · n = 39 sessions from 29 mice
  • Cortical LFP spectral analysis from Neuropixels · mouse (C57BL/6J) · n = 45 sessions from 34 mice
Methods & tools
Neuropixels 1.0, Kilosort 2.0, Open Ephys, DeepLabCut, Allen Mouse Brain CCFv3, SciPy, pingouin, ketanserin, psilocybin
Reproducibility gaps
Raw data are to be released in NWB format on a DANDI Archive only after acceptance for publication; no accession is given. Statistical tables are in supplementary spreadsheets.
Limitations (5)
  • The prefrontal cortex burst effects did not survive FDR correction and are interpreted as trends only. · stated by the authors
  • Geniculate nuclei and CA2 were sampled in only 2 of 8 Ket+Psi sessions, so ketanserin dependence could not be tested there. · stated by the authors
  • Firing rate drifted upward over the session in saline animals, attributed to head-fixation stress or probe effects. Pooling pyramidal tract and intratelencephalic neurons may dilute prefrontal signals. · stated by the authors
  • The design has no ketanserin-only control. Ketanserin itself suppressed firing broadly, which complicates reading Ket+Psi as a clean 5-HT2A block. · noted in this summary
  • The Ket+Psi group is small (8 sessions; 5 mice with paired saline sessions), and ketanserin blocks both 5-HT2A and 5-HT2C receptors, so the design cannot separate 2A from 2C contributions; the authors frame the dependence as 'at least partial'. · noted in this summary

Read this if you study psychedelic circuit effects and want brain-wide single-unit evidence that burst coding, not mean firing rate, shifts in thalamus and hippocampus.

Citations
1

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