MDMA enhances prefrontal plasticity and representational drift during fear extinction

Fear extinction requires dynamic updating of cortical representations, yet the neural mechanisms underlying successful extinction remain poorly understood. Some psychoactive substances induce structural plasticity in medial prefrontal cortex (mPFC), possibly underlying their therapeutic potential. Here we investigated whether MDMA, which enhances fear extinction, induces prefrontal structural and functional plasticity, and measured its effects on ensemble representations during extinction. Longitudinal two-photon microscopy revealed that MDMA increased spine density and spinogenesis across prefrontal subregions. Miniscope Ca²⁺ imaging in infralimbic cortex (IL) during fear extinction revealed that IL became more correlated with the suppression of freezing behavior, consistent with a strengthening of its role in extinction. Longitudinal cell registration demonstrated accelerated representational drift across days in MDMA-treated mice; this effect was strongest in a functionally defined subpopulation of neurons that showed suppression of activity to conditioned cues. These findings demonstrate that MDMA facilitates structural and functional neuroplasticity, potentially underlying its enhancement of extinction learning.