Circuit and subcellular basis of MDMA effects on innate and learned fear

PROJECT SUMMARY Methylenedioxy-methamphetamine (MDMA) enhances the extinction of learned threat associations in mice and humans and has recently demonstrated efficacy in augmenting psychotherapy in posttraumatic stress disorder (PTSD). However, the mechanism of this effect is unknown. Understanding the neural circuits responsible for MDMA-enhanced threat extinction may facilitate the development of new treatments of anxiety and trauma- related disorders. In this application, we utilize longitudinal two-photon imaging of dendritic spines to characterize the structural changes in frontal cortex occurring with MDMA and how they relate to the 5HT2A receptor which is both directly and indirectly activated by MDMA. We use microendoscope calcium imaging and to understand how neural populations in the infralimbic cortex represents innate and learned fear differently after MDMA treatment. Subsequently, we directly manipulate plasticity optogenetic suppression of CaMKII signaling affects subsequent innate and learned fear behaviors. Finally, we utilize engram mapping and optogenetics to stimulate behaviorally specific ensembles of neurons in infralimbic cortex during MDMA exposure. We hypothesize that activation of distinct ensembles will differentially affect the subsequent lasting effects of MDMA on behavior. Thus, this study applies cutting edge optical neurophysiology approaches to a critical mechanistic question: delineating the frontal cortical circuit- and subcellular adaptations to MDMA that underlie its diverse effects on innate and learned fear.