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bioRxiv · 10.1101/2025.05.26.655791

Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin

Joseph, K.·Collins, J.·Genovese, T.·Maxwell, M.·Lieberman, J. A.·Osten, P.
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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.

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Joseph, K., Collins, J., Genovese, T., Maxwell, M., Lieberman, J. A., Osten, P.. 2025-05-30. Converging pathways: shared brain circuitry engaged by monoaminergic antidepressants, ketamine and psilocybin. https://doi.org/10.1101/2025.05.26.655791

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