Thread by @kwanalexc

Our latest study identifies a specific cell type and receptor essential for psilocybin’s long-lasting neural and behavioral effects 🍄🔬🧠🐁

Led by Ling-Xiao Shao and @ItsClaraLiao

Funded by @NIH @NIMHgov

📄Read in @Nature -

1/12nature.com/articles/s4158…

Pyramidal cells in the neocortex are not all the same. There are major PT (pyramidal tract) and IT (intratelencephalic) subtypes. Interestingly, both subtypes express the serotonin 2A receptor 🧬.

What roles do they play for psilocybin’s action?

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To start, we look at structural plasticity.

After a single dose of psilocybin, both PT and IT neurons in the medial frontal cortex sprout new dendritic spines, indicating neural remodeling.

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But when it comes to behavior, the two cell types diverge.

Normally, psilocybin can reverse stress-related behaviors. When we inactivate PT neurons before administering psilocybin, the drug’s ameliorating effects disappeared. Silencing the IT neurons had no effect.

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Interestingly, neither the PT nor the IT manipulations affected the acute head-twitch response.

The results highlight PT neurons as key to the long-term antidepressant-like effects of psilocybin.

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Digging deeper, there are other cell-type specific features.

Psilocybin increases calcium activity in the apical dendrites of PT neurons, but not IT neurons.

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And while the spiking response is heterogeneous, we find a subset of frontal cortical PT neurons that show strong activation following psilocybin administration.

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Getting back to the receptor –

It has long been debated whether serotonin 2A receptor is needed. We took a precise approach, using a conditional knockout mouse to show that deleting the receptor in frontal cortex abolishes psilocybin’s long-term behavioral effects.

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Moreover, deleting the serotonin 2A receptor specifically in PT neurons eliminates the psilocybin-evoked structural remodeling.

These are strong evidence supporting the role of serotonin 2A receptors in psychedelic drug action.

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To summarize: same receptor (5-HT2A), different circuits.

The short- and long-term effects of psilocybin are mediated by different circuits, with the PT neurons in frontal cortex sitting at the core of the long-term response.

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The research is possible with funding from @NIH @NIMHgov

Additional support from @NIDAnews @OneMindOrg and the Source Research Foundation 🙏

A collaborative effort between my team at @CornellBME @CornellEng and @kaistpr @AliciaYChe @YalePsych @YaleMed 🤝

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@NIH @NIMHgov @NIDAnews @OneMindOrg @CornellBME @CornellEng @kaistpr @AliciaYChe @YalePsych @YaleMed We also wrote a short Research Briefing piece highlighting the key findings. Check it out here:



12/12doi.org/10.1038/d41586…

@NIH @NIMHgov @NIDAnews @OneMindOrg @CornellBME @CornellEng @kaistpr @AliciaYChe @YalePsych @YaleMed Bonus: A view-only link for the article: rdcu.be/ef9Nv