Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin
Pavel Osten, K Sunny Joseph, Jane Collins, Thomas S. Genovese, Margaret Maxwell, J Lieberman
bioRxiv (Cold Spring Harbor Laboratory) May 30, 2025 preprint DOI: 10.1101/2025.05.26.655791 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Population | Mice |
| Interventions | Ketamine psilocybin fluoxetine |
| Topics | Ketamine Psilocybin Esketamine |
| Keywords | Monoaminergic Hallucinogen |
| Key findings | A shared limbic subcortico-cortical circuit underlies antidepressant efficacy, with acute activation of frontal cortex by ketamine and high-dose psilocybin but only chronic activation by fluoxetine and psilocybin microdosing. |
Abstract
Abstract Ketamine has transformed depression treatment by providing therapeutic relief within a single day, unlike monoaminergic antidepressants that require weeks to take effect. Here, we conducted whole-brain screening in mice to compare drug-evoked c-fos expression—acting as a marker of brain activity leading to protein synthesis-dependent forms of plasticity—following treatment with monoaminergic antidepressants, ketamine and psilocybin. Our findings reveal a shared limbic brain circuit comprising subcortical and frontal cortical regions, with a key distinction: c-fos-based activity in the prelimbic and infralimbic frontal cortex—areas strongly implicated in depression—was acutely induced by ketamine and high-dose psilocybin, but emerged only after chronic dosing with the selective serotonin reuptake inhibitor fluoxetine or psilocybin microdosing. These results suggest the existence of a core limbic subcortico-cortical circuit underlying antidepressant efficacy, provide mechanistic insight into the delayed therapeutic effects of monoaminergic antidepressants, and reveal a close similarity in brain activity evoked by monoaminergic antidepressants and psilocybin microdosing.
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
Cites 16
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
- Glutamate and the Neural Basis of the Subjective Effects of Ketamine Archives of General Psychiatry February 1, 2008
- Deep posteromedial cortical rhythm in dissociation Nature September 16, 2020
and 11 more in the library