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UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice

Neuropsychopharmacology volume 48, pages 1798–1807 (2023)Cite this article

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Abstract

The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2+/−;Ai14+ mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse.

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Fig. 1: Methodological workflow for the identification and validation of neural populations activated by psilocybin across contexts.
Fig. 2: Main effects of context and psilocybin on c-Fos-IF.
Fig. 3: Modest interactions between context and psilocybin.
Fig. 4: Network analysis of neural populations sensitive to psilocybin.

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Data availability

Custom scripts and detailed protocols are at https://github.com/b-heifets/UNRAVEL. Raw data (~30GB/hemisphere) are available upon request.

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Acknowledgements

The authors offer their sincere gratitude to Dr Michel B. Hell for his help with adapting the CLIJx plugin to allow for fractional assignment of cells overlapping region boundaries during 3D object counting on the GPU, Mr Daniel F. Cardozo Pinto for helpful discussions, and Miss Zahra Rastegarmoghaddam for her assistance with initial adaptation of an Excel template for use with the LSFM atlas. We also thank the Wu Tsai Neuroscience Center, Neuroscience Microscopy Service for initial guidance on light sheet microscopy (S10OD025091-01) and help collecting pilot data. Figure 1 was created with BioRender.

Funding

XZ and LMW acknowledge support from the National Institute of Drug Abuse under award P50DA042012. MBP acknowledges support from the National Institute of Drug Abuse under award K99DA056573.

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  1. These authors contributed equally: Daniel Ryskamp Rijsketic, Austen B. Casey.

Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Daniel Ryskamp Rijsketic, Austen B. Casey, Tuuli M. Hietamies, Grecia Ramirez-Ovalle & Boris D. Heifets

  2. Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Daniel A. N. Barbosa & Casey H. Halpern

  3. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA

    Xue Zhang, Matthew B. Pomrenze, Leanne M. Williams, Robert C. Malenka & Boris D. Heifets

  4. Nancy Pritzker Laboratory, Stanford University, Stanford, CA, 94305, USA

    Matthew B. Pomrenze & Robert C. Malenka

  5. Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC) Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Leanne M. Williams

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Contributions

DRR: Writing—original draft, conceptualization, investigation, data curation, formal analysis, methodology, software, validation, visualization. ABC: Writing—original draft, conceptualization, investigation, data curation, formal analysis, methodology, software, validation, visualization. DANB: Conceptualization, methodology, software, writing—review & editing. XZ: Formal analysis, methodology, software, visualization, writing—review & editing. TMH: Conceptualization, writing—review & editing. GRO: Software. MP: Conceptualization, methodology, writing—review & editing. CHH: Writing—review & editing, supervision. LMW: Writing—review & editing, supervision. RCM: Writing—review & editing, supervision. BDH: Writing—review & editing, conceptualization, methodology, funding acquisition, project administration, resources, supervision.

Corresponding author

Correspondence to Boris D. Heifets.

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Competing interests

LMW has served as a scientific advisor for One Mind Psyberguide, a member of the executive advisory board for the Laureate Institute for Brain Research and holds patent 16921388 (Systems and Methods for Detecting Complex Networks in MRI Image Data) unrelated to the present study. RCM is on the scientific advisory boards of MapLight Therapeutics, Bright Minds, MindMed, Cyclerion, AZTherapies, and Aelis Farma. BDH is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant for Clairvoyant Therapeutics and Vine Ventures. The remaining authors have nothing to disclose.

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Rijsketic, D.R., Casey, A.B., Barbosa, D.A.N. et al. UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. Neuropsychopharmacol. 48, 1798–1807 (2023). https://doi.org/10.1038/s41386-023-01613-4

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