FUNCTION OF THE ANTERIOR INSULAR CORTEX IN THE IMPACT OF A SINGLE PSYCHEDELIC EXPOSURE ON ANXIETY

Anxiety affects ~20% of adults and remain insufficiently treated, as about a third of patients do not respond to current therapies. The anterior insular cortex (insula) integrates interoceptive and affective signals and is consistently reported as hyperactive in patients with anxiety disorders. It receives dense serotonergic innervation and expresses 5‑HT1A/2A receptors, key modulators of mood. Psychedelics including 5-MeO-DMT engage these receptors, producing persistent anxiolytic effects in patients.We hypothesize that long-lasting anxiolysis induced by psychedelics is mediated by reduced activity of 5-HT1A+ insula neurons. To test this, we performed behavioral and neural measures in male and female C57BL/6J mice. One week after 5-MeO-DMT injection (20 mg/kg), mice exhibited reduced anxiety-like behavior in the elevated plus maze. At this long-term time point, photometry recordings revealed decreased calcium activity of 5-HT1A+ insula neurons during exploration of anxiogenic compartments, relative to vehicle. Moreover, immediately after 5-MeO-DMT injection, we observed a selective emergence of atypical calcium transients (“giant transients”), diverging from canonical transients by marked increase in frequency. Interestingly, acute single-units electrophysiological and miniscope recordings from 5‑HT1A+ neurons suggest an overall reduction in neuronal activity. Along the acute appearance of giant transients, these data suggest a reorganization of neural activity in the insula. Consistently, electrophysiological recordings immediately after 5‑MeO-DMT showed increased gamma-band power (30–80 Hz) and a robust increase in theta phase–gamma amplitude coupling. Altogether, these data indicate that 5-MeO-DMT induces rapid and sustained reconfiguration of insula neural dynamics likely supporting anxiolysis, potentially via 5‑HT1A signaling.