Abstract
PTSD, posttraumatic stress disorder, Trauma
SEPARATION, EVENTS
The authors declare no competing financial interests.Author contributions: J.M.W., Y.X., B.K., and D.R.B. designed research; J.M.W., Y.X., B.O., D.M., and D.R.B. performed research; J.M.W. and Y.X. analyzed data; J.M.W. and D.R.B. wrote the paper.This work was supported by the Clinical Research Priority Program of the University of Zurich for the CRPP “Synapse & Trauma.” D.R.B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No. ERC-2018 CoG-816564 ActionContraThreat). The Wellcome Centre for Human Neuroimaging is funded by core funding from the Wellcome (203147/Z/16/Z).J.M.W. and Y.X. contributed equally to this work.Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP)9 signaling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signaling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomized controlled trial with 101 (50 females) human participants. We find no impact of the drug in our preregistered analyses. Exploratory 