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MicroRNA regulation of persistent stress-enhanced memory.

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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Sillivan SE,Jamieson S,de Nijs L,Jones M,Snijders C,Klengel T,Joseph NF,Krauskopf J,Kleinjans J,Vinkers CH,Boks MPM,Geuze E,Vermetten E,Berretta S,Ressler KJ,Rutten BPF,Rumbaugh G,Miller CA

doi

10.1038/s41380-019-0432-2

subject

Has Abstract

pub_date

2020-05-01 00:00:00

pages

965-976

issue

5

eissn

1359-4184

issn

1476-5578

pii

10.1038/s41380-019-0432-2

journal_volume

25

pub_type

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