期刊
BIOLOGICAL PSYCHIATRY
卷 81, 期 12, 页码 979-989出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2016.12.021
关键词
Anxiety- and trauma-related disorders; Basolateral amygdala; Fear; MicroRNAs; PI3K/AKT; Signaling cascade modulation
资金
- Austrian Science Fund (FWF) [SFB F4410, SFB F4411, P25375-B24]
- Signal Processing In Neurons (FWF) [DK W-1206]
- European Molecular Biology Organization (ASTF) [459-2015]
- National Health and Medical Research Council [1069570]
- National Institute of Mental Health [R21MH103812]
- Austrian Science Fund (FWF) [W1206, P25375] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 25375] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1069570] Funding Source: NHMRC
BACKGROUND: MicroRNA (miRNA)-mediated control of gene expression suggests that miRNAs are interesting targets and/or biomarkers in the treatment of anxiety-and trauma-related disorders, where often memory-associated gene expression is adversely affected. METHODS: The role of miRNAs in the rescue of impaired fear extinction was assessed using the 129S1/SvlmJ (S1) mouse model of impaired fear extinction. miRNA microarray analysis, reverse transcription polymerase chain reaction, fluorescent in situ hybridization, lentiviral overexpression, and Luciferase reporter assays were used to gain insight into the mechanisms underlying miRNA-mediated normalization of deficient fear extinction. RESULTS: Rescuing impaired fear extinction via dietary zinc restriction was associated with differential expression of miRNAs in the amygdala. One candidate, miR-144-3p, robustly expressed in the basolateral amygdala, showed specific extinction-induced, but not fear-induced, increased expression in both extinction-rescued S1 mice and extinction-intact C57BL/6 (BL6) mice. miR-144-3p upregulation and effects on subsequent behavioral adaption was assessed in S1 and BL6 mice. miR-144-3p overexpression in the basolateral amygdala rescued impaired fear extinction in S1 mice, led to enhanced fear extinction acquisition in BL6 mice, and furthermore protected against fear renewal in BL6 mice. miR-144-3p targets a number of genes implicated in the control of plasticity-associated signaling cascades, including Pten, Spred1, and Notch1. In functional interaction studies, we revealed that the miR-144-3p target, PTEN, colocalized with miR-144-3p in the basolateral amygdala and showed functional down-regulation following successful fear extinction in S1 mice. CONCLUSIONS: These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders.
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