Psilocybin reduces fear memory and restores neuroplasticity in the hippocampus and medial prefrontal cortex

BACKGROUND: Posttraumatic stress disorder (PTSD) and major depressive disorder are often comorbid in humans. Psilocybin reportedly has beneficial therapeutic effects on depression, possibly by promoting neuroplasticity. PTSD is associated with the dysregulation of neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC). We hypothesized that psilocybin might reduce fear memory by promoting neuroplasticity in the hippocampus and mPFC. AIMS: We investigated the effects of psilocybin on fear memory and explored its underlying mechanisms. We generated a mouse model of PTSD via auditory-cued fear conditioning and treated the mice with either vehicle or psilocybin (2.5 mg/kg, intraperitoneal) on day 0. Fear memory was assessed by the percentage of freezing time in response to conditioned stimuli. Fear memory tests were conducted on days 1, 6, and 7, after which the mice were sacrificed. To investigate the role of neuroplasticity in mediating the effects of psilocybin on fear memory, we assessed structural neuroplasticity and neuroplasticity-associated marker protein levels in the hippocampus and mPFC 7 days after a single dose of psilocybin. RESULTS: Psilocybin reduced the cue-induced fear response on days 1, 6, and 7. Psilocybin ameliorated the fear conditioning-induced decreases in neuroplasticity in the hippocampus and mPFC. Through Golgi-Cox staining, Western blotting, and immunofluorescence staining, we found that psilocybin increased dendritic branches and spine density, upregulated GluR1 and synapsin-1, enhanced brain-derived neurotrophic factor and mammalian target of rapamycin signaling, and promoted neurogenesis. CONCLUSIONS: A single dose of psilocybin reduces both the rapid and sustained fear memory in mice, at least in part by restoring neuroplasticity in the hippocampus and mPFC. These findings indicate that psilocybin has significant potential for use in the treatment of PTSD and other mental disorders characterized by fear memory.