MDMA enhances prefrontal plasticity and representational drift during fear extinction
Nitzan Geva, Sarah J. Jefferson, Emi Krishnamurthy, Tanner L. Anderson, Jocelyne Rondeau, Patrick H. Wehrle, Axel Fogaça Rosado, Christopher Pittenger, John H. Krystal, Alfred P. Kaye
bioRxiv (Cold Spring Harbor Laboratory) March 8, 2026 preprint DOI: 10.64898/2026.03.06.710094 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Longitudinal |
|---|---|
| Population | Mice |
| Intervention | MDMA |
| Topics | MDMA Neuroplasticity |
| Keywords | Extinction optical mineralogy Prefrontal cortex Infralimbic cortex Hippocampus Cognition Neural activity Freezing behavior Structural plasticity |
| Key findings | MDMA increases spine density and spinogenesis in prefrontal subregions, strengthens the correlation of infralimbic cortex activity with freezing suppression, and accelerates representational drift in a functionally defined neuronal subpopulation. |
Abstract
Abstract 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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cites 18
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Translational Psychiatry September 15, 2015
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