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Mol Psychiatry. 2019 May 29. doi: 10.1038/s41380-019-0432-2. [Epub ahead of print]

MicroRNA regulation of persistent stress-enhanced memory.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
2
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
3
School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands.
4
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
5
Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
6
Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
7
Research Centre for Military Mental Healthcare, Ministry of Defence, Utrecht, The Netherlands.
8
Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
9
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA. cmiller@scripps.edu.
10
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA. cmiller@scripps.edu.

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.

PMID:
31142820
DOI:
10.1038/s41380-019-0432-2

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