Abstract
Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood–brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.
Highlights
Learning to predict threat is a fundamental ability of many biological organisms, yet in anxiety disorders dysfunctional overprediction of threat causes tremendous suffering
Threat memory was attenuated by ~ 60% in the doxycycline as compared to placebo group. This initial analysis did not take into account that the sequence of CS+ and CS − was randomised for each participant, and might have been slightly different between the two groups. This is why we Blocking human fear memory with doxycycline replicated these results in a linear mixed effects (LME) model with trial number as predictor across CS types
We addressed inhibition of human fear conditioning with the matrix metalloproteinase (MMP) inhibitor doxcycyline
Summary
Learning to predict threat is a fundamental ability of many biological organisms, yet in anxiety disorders dysfunctional overprediction of threat causes tremendous suffering. Evidence has accumulated for a role of extracellular matrix in memory formation.[7,8] In terms of its structure, extracellular matrix is organised in perineuronal nets.[9] Their integrity is crucial for memory storage, including threat memory.[10,11,12] Functionally, the signalling pathway that induces LTP appears to involve extracellular enzymes, and matrix metalloproteinase 9 (MMP-9).[7] In slices, MMP-9 inhibition or knockout reduces long-term potentiation.[13,14,15,16] Interestingly, active MMP-9 alone is sufficient to induce LTP.[13,14] In vivo, MMP-9 inhibition appears to impact on spatial/contextual memory in nonhuman mammals.[17,18] While the precise mechanism by which MMP-9 takes part in synaptic circuit remodelling remains elusive,[7] these findings suggest that MMP-9 may be required for formation of human fear memories. While fear-potentiated startle scales with CS/US association strength,[30] SCR are suggested to reflect CS-specific associability,[31,32] which is based on a weighted average of surprise about the previous outcomes following this CS.[33]
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