UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice.
Daniel Ryskamp Rijsketic, Austen B Casey, Daniel A. N. Barbosa, Xue Zhang, Tuuli M. Hietamies, Grecia Ramirez-Ovalle, Matthew B Pomrenze, Casey H. Halpern, Leanne M Williams, Robert C. Malenka, Boris D. Heifets
Neuropsychopharmacology November 1, 2023 DOI: 10.1038/s41386-023-01613-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice (TRAP2+/-;Ai14+ and other strains) |
| Interventions | Psilocybin saline |
| Topics | Psilocybin |
| Keywords | Psychedelics Brain research Neural networks |
| Citations | 49 |
| Key findings | Psilocybin produced widespread, context-independent changes in neural activity and disrupted brain network modularity and intermodular co-activity in mice. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 33
- Psilocybin desynchronizes the human brain. Nature August 1, 2024
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications. Brain Sciences January 25, 2025
- Structural neural plasticity evoked by rapid-acting antidepressant interventions. Nature Reviews Neuroscience February 1, 2025
- Cardiovascular safety of psychedelic medicine: current status and future directions Pharmacological Reports October 24, 2023
and 28 more in the library
Cites 29
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
and 24 more in the library