MicroRNA regulation of persistent stress-enhanced memory.

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

doi:10.1038/s41380-019-0432-2

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 one 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 postmortem 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.

Highlights

Unlike memory formation, mechanisms supporting long-lasting, remote memory are largely unknown, yet highly relevant to psychiatric disorders marked by persistent, unwanted memories, such as posttraumatic stress disorder (PTSD)
Tissue was isolated 30 days after training to identify miRNAs in SS mice contributing to enhanced memory strength through persistent change following stress-enhanced fear learning (SEFL), not miRNA changes dynamically induced by the act of memory retrieval
Utilizing a stress-enhanced fear learning protocol we developed[4], that results in differential stress susceptibility in an inbred mouse strain commonly used in neuroscience, c57bl/6, we identified 42 miRNAs differentially expressed in the amygdala between susceptible and resilient mice one month after training

Summary

Introduction

Unlike memory formation, mechanisms supporting long-lasting, remote memory are largely unknown, yet highly relevant to psychiatric disorders marked by persistent, unwanted memories, such as posttraumatic stress disorder (PTSD). PTSD is a chronic, debilitating disorder in which patients exhibit heightened, perseverant and extinction-resistant memories of trauma[1]. A form of cognitive behavioral therapy (CBT) that utilizes extinction of fearful memories, is considered the gold standard treatment. Many patients are resistant or experience exacerbated symptoms with exposure therapy and, of those who respond, most retain their PTSD diagnosis[3]. Development of adjunctive pharmacotherapies to enhance success of the various forms of CBT is needed. There is a need to better understand the mechanisms that determine differential responses to stress and how those responses persist for extended periods of time

Methods

Results

Conclusion