Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin
Ling-Xiao Shao, Pasha A. Davoudian, Alex C. Kwan
ACS Chemical Neuroscience January 11, 2023 DOI: 10.1021/acschemneuro.2c00637 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | Male and female mice |
| Interventions | Psilocybin subanesthetic ketamine saline control |
| Topics | Ketamine Psilocybin Esketamine |
| Keywords | Hallucinogen Gene expression Pharmacology |
| Citations | 131 |
| Key findings | Psilocybin and ketamine produce comparable elevations in c-Fos expression across many brain regions, with drug-preferential differences in select areas, and endogenous Grin2a and Grin2b levels predict cortical sensitivity to drug-evoked neural plasticity. |
Abstract
Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.
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 94
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- Psychedelics and Neural Plasticity: Therapeutic Implications. Journal of Neuroscience November 1, 2022
- Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors. Nature June 1, 2025
- Acute psilocybin enhances cognitive flexibility in rats Neuropsychopharmacology February 20, 2023
- Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments Proceedings of the National Academy of Sciences November 27, 2023
and 89 more in the library
Cites 34
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
and 29 more in the library