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J Neurosci. 2019 Oct 14. pii: 1285-19. doi: 10.1523/JNEUROSCI.1285-19.2019. [Epub ahead of print]

Threat memory reminder under matrix metalloproteinase 9 inhibitor doxycycline globally reduces subsequent memory plasticity.

Author information

1
Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, 8032 Zurich, Switzerland dominik.bach@uzh.ch.
2
Neuroscience Centre Zurich, University of Zurich, 8057 Zurich, Switzerland.
3
Wellcome Centre for Human Neuroimaging and Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, London WC1N 3BG, UK.
4
Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, 8032 Zurich, Switzerland.
5
Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, 8032 Zurich, Switzerland.
6
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.

Abstract

Associative memory can be rendered malleable by a reminder. Blocking the ensuing re-consolidation process is suggested as a therapeutic target for unwanted aversive memories. Matrix metalloproteinase (MMP)-9 is required for structural synapse remodelling involved in memory consolidation. Inhibiting MMP-9 with doxycycline is suggested to attenuate human threat conditioning. Here, we investigate whether MMP-9 inhibition also interferes with threat memory re-consolidation. N=78 male and female human participants learned the association between two visual conditioned stimuli (CS+) and a 50% chance of an unconditioned nociceptive stimulus (US), and between CS- and the absence of US. On day 7, one CS+ was reminded without reinforcement 3.5 hours after ingesting either 200 mg doxycycline, or placebo. On day 14, retention of CS memory was assessed under extinction, by fear-potentiated startle. Contrary to our expectations, we observed a greater CS+/CS- difference in participants who were reminded under doxycycline, compared to placebo. Participants who were reminded under placebo showed extinction learning during the retention test, which was not observed in the doxycycline group. There was no difference between the reminded and the non-reminded CS+ in either group. In contrast, during re-learning after the retention test, CS+/CS- difference was more pronounced in the placebo than the doxycycline group. To summarize, a single dose of doxycycline appeared to have no specific impact on re-consolidation, but to globally impair extinction learning, and threat re-learning, after drug clearance.SIGNIFICANCE STATEMENTMMP-9 inhibition appears to attenuate memory consolidation. It could also be a target for blocking reconsolidation. Here, we test this hypothesis in human threat conditioning. We find that doxycycline has no specific impact on a reminded cue, but confers a global reduction in extinction learning and threat learning beyond the clearance of the drug. This may point towards a more long-lasting impact of doxycycline treatment on memory plasticity.

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