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Serotonin and psilocybin activate 5-HT1B receptors to suppress cortical signaling through the claustrum

Summary

Researchers found that serotonin and psilocybin (the active compound in magic mushrooms) work through the same brain mechanism to suppress certain neural signals in a brain region called the claustrum. This region controls how different parts of the cortex communicate with each other. The study shows that psilocybin directly targets serotonin 5-HT1B receptors to quiet down signals from one brain area to another, which may explain how psychedelics change cortical network activity and alter consciousness.

Background

The claustrum is a subcortical nucleus with widespread reciprocal connections to the cerebral cortex and plays a role in cortical network states during sleep and waking. The claustrum receives rich serotonergic innervation and expresses serotonin receptors. Psilocybin is suggested to disrupt cortex-wide network states partly through claustrum modulation.

Objective

To investigate the role of serotonin and psilocybin in modulating cortical signaling through the claustrum, specifically examining how these substances affect the anterior cingulate cortex (ACC) inputs to claustrum neurons projecting to parietal association cortex (PtA).

Results

Serotonin activated presynaptic 5-HT1B receptors on ACC terminals to suppress glutamate release onto claustrum neurons, including those projecting to PtA. Psilocybin similarly suppressed ACC signaling through 5-HT1B-dependent mechanisms in vivo, and this suppression persisted for at least 24 hours after drug administration.

Conclusion

Serotonin provides gain-control of cortical input to the claustrum via 5-HT1B receptors, and psilocybin directly targets this mechanism to modulate downstream cortical network states. These findings establish a synaptic basis for how psychedelics may alter cortical connectivity through claustrum modulation.
  • Published in:Nature Communications,
  • Study Type:Experimental Research,
  • Source: PMID: 40830107, DOI: 10.1038/s41467-025-62980-8
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