MicroRNA regulation of persistent stress-enhanced memory

Stephanie E. Sillivan, Sarah Jamieson, Laurence de Nijs, Meghan Jones, Clara Snijders, Torsten Klengel, Nadine F. Joseph, Julian Krauskopf, Jos Kleinjans, Christiaan H. Vinkers, Marco P. M. Boks, Elbert Geuze, Eric Vermetten, Sabina Berretta, Kerry J. Ressler, Bart P. F. Rutten, Gavin Rumbaugh, Courtney A. Miller

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Abstract

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.
Original languageEnglish
JournalMolecular Psychiatry
DOIs
Publication statusE-pub ahead of print - 29 May 2019

Cite this

Sillivan, S. E., Jamieson, S., de Nijs, L., Jones, M., Snijders, C., Klengel, T., ... Miller, C. A. (2019). MicroRNA regulation of persistent stress-enhanced memory. Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0432-2