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MDMA enhances prefrontal plasticity and representational drift during fear extinction
Biorxiv : the Preprint Server for Biology
|March 23, 2026
Summary
MDMA enhances fear extinction by promoting neuroplasticity in the medial prefrontal cortex (mPFC). This involves increasing neuronal connections and altering neural representations during the extinction learning process.
Area of Science:
- Neuroscience
- Psychopharmacology
Background:
- Fear extinction is crucial for treating anxiety disorders but its neural mechanisms are unclear.
- Medial prefrontal cortex (mPFC) structural plasticity may underlie therapeutic effects of some psychoactive substances.
Purpose of the Study:
- Investigate if MDMA enhances fear extinction by inducing structural and functional plasticity in the mPFC.
- Examine MDMA's effects on neural ensemble representations during fear extinction.
Main Methods:
- Longitudinal two-photon microscopy to assess structural changes (spine density, spinogenesis) in the mPFC.
- Miniscope Ca²⁺ imaging in the infralimbic cortex (IL) during fear extinction.
- Longitudinal cell registration to track neuronal representational drift.
Main Results:
- MDMA significantly increased spine density and spinogenesis in mPFC subregions.
- IL activity became more correlated with freezing suppression during extinction in MDMA-treated mice.
- MDMA accelerated neuronal representational drift, particularly in neurons suppressing activity to conditioned cues.
Conclusions:
- MDMA facilitates structural and functional neuroplasticity in the mPFC.
- These neuroplastic changes are associated with enhanced fear extinction learning.
- MDMA's effects on mPFC plasticity may explain its therapeutic potential for anxiety disorders.
