Psilocin, the active metabolite of psilocybin, produces sex-specific and lasting changes in central amygdala (CeA) activity and reactivity to an aversive stimulus in mice. Acutely, psilocin increased CeA activity in both sexes and increased stimulus-specific CeA reactivity in females but not males. Over time, psilocin decreased CeA reactivity in males from 2 to 28 days after administration, while no such decrease occurred in females. Behavioral responses to the aversive stimulus also showed sex-dependent changes in threat responding, without affecting exploratory behavior or locomotion. These findings indicate that a single dose of psilocin induces enduring, sex-specific alterations in CeA function and threat-related behavior.
Psilocin, the active metabolite of psilocybin, alters brain activity in rats in a sex-specific manner. It increases activity in the paraventricular nucleus of the thalamus (PVT) and selectively engages PVT projections to the central amygdala (CeA) in females but not males. Psilocin enhances PVT reactivity to an aversive stimulus, driven by passive responders, and prevents time-dependent reductions in stimulus-evoked activity in PVT→CeA neurons in females but not males, driven by active responders. These findings identify sex-specific modulation of thalamic-limbic circuitry by psilocin, advancing understanding of how psychedelics modulate emotional brain circuits.