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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Web of Science)

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
Pages (from-to)965-976
Number of pages12
JournalMolecular Psychiatry
Volume25
Issue number5
Early online date29 May 2019
DOIs
Publication statusPublished - May 2020

Keywords

  • SYNAPTIC-TRANSMISSION
  • FEAR-EXTINCTION
  • COCAINE INTAKE
  • AMYGDALA
  • EXPRESSION
  • RESILIENCE
  • PLASTICITY
  • LIFETIME
  • ANXIETY
  • TARGET

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