Abstract
The psychedelic psilocybin has shown therapeutic potential, yet underlying neural mechanisms remain poorly understood. We investigated the impact of psilocin—the active metabolite of psilocybin—on basal activity and reactivity within the paraventricular nucleus of the thalamus (PVT) and PVT projections to central amygdala (CeA) in rats. Psilocin administration increased PVT c-Fos expression and selectively engaged PVT→CeA neurons in females, but not males. Psilocin enhanced PVT reactivity to an aversive air-puff stimulus, with effects primarily driven by passive responders. In PVT→CeA neurons, psilocin prevented time-dependent reductions in stimulus-evoked activity and maintained reactivity across timepoints in females but not males. The sustained engagement of PVT→CeA circuitry was driven by active responders. These findings identify sex-specific modulation of thalamic-limbic circuitry and behavior by psilocin, implicating PVT→CeA circuitry in the neural and behavioral effects of psychedelic compounds, advancing our understanding of how psychedelics modulate emotional brain circuits to further inform potential therapeutic mechanisms.
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All data generated in this study, including a source data file containing raw data values for each figure, have been deposited in the Dryad database https://doi.org/10.5061/dryad.fbg79cp7b. Source data are provided with this paper.
Code availability
Custom-written MATLAB code and resulting MATLAB structures have been made available on the Dryad database https://doi.org/10.5061/dryad.fbg79cp7b.
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Acknowledgements
This work was supported by National Institute of Health grants AA026858 (M.A.H.), GM135095 (D.P.E.), AA007573 (S.G.Q.), AA030493 (S.G.Q.), and by the Brain and Behavior Research Foundation NARSAD Young Investigator Award (M.A.H.).
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D.P.E. contributed to the initial conception, experimental design, apparatus design, surgical procedures, behavioral recording, histology, data analysis, custom code, data visualization, the initial draft of the manuscript, and manuscript editing. J.L.H. contributed to the behavioral recording, behavioral analysis, a section in methods, and manuscript editing. S.G.Q. contributed to histological analyses, schematic illustrations, and manuscript editing. C.S.R. contributed to histology. D.T. contributed to histology. M.E.S. contributed to histology. M.W.H. contributed to histology. C.W.H. contributed to the behavioral recording and manuscript editing. M.A.H. contributed to the initial conception, experimental design, behavioral assay, and acquisition of funds.
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Effinger, D.P., Hoffman, J.L., Quadir, S.G. et al. Sex-specific increased reactivity of the PVT and prolonged PVT→CeA circuit engagement following psilocin administration. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71481-1
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DOI: https://doi.org/10.1038/s41467-026-71481-1
