MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice

Murphy, Conor P.; Li, Xiang; Maurer, Verena; Oberhauser, M.; Gstir, Ronald; Wearick-Silva, Luís Eduardo; Viola, Thiago Wendt; Schafferer, Simon; Grassi‐Oliveira, Rodrigo; Whittle, Nigel; Hüttenhofer, Alexander; Bredy, Timothy W.; Singewald, Nicolas

doi:10.1016/j.biopsych.2016.12.021

Cited by 62 publications

(42 citation statements)

References 55 publications

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“…It is now widely accepted that NOTCH transcription and translation is negatively regulated by microRNAs, which consequently affects the intensity of NOTCH signaling (Dias et al, ). This is in line with Murphy et al () who showed that impaired fear extinction, as frequently observed in PTSD patients, could be rescued by targeting genes in plasticity‐associated signaling cascades (i.e., NOTCH) to increase microRNA‐controlled gene expression in the amygdala. However, their findings are based on brain tissue, and future research is needed to determine whether similar effects can be found in humans and in peripheral tissues (e.g., blood).…”

Section: Discussionsupporting

confidence: 88%

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts

et al. 2018

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The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans‐membrane receptor proteins (NOTCH1–4), constitutes an evolutionarily well‐conserved intercellular communication pathway (involved, e.g., in cell–cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1–4 (investigated by microarray) and genomic methylation of saliva‐derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH‐related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi‐)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.

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Section: Discussionsupporting

confidence: 88%

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts

et al. 2018

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“…Moreover, aberrant miR-144 expression is associated with the pathogenesis of psychiatric disorders. In fear extinction-impaired animals, over expression of miR-144 in the amygdala can successfully rescue fear extinction memory by targeting Pten, Notch1 and Spred1, a group of genes important for the control of fear extinction [100], highlighting the significance of miR-144 for the memory-related activities.…”

Section: Function Of Mir-144/451 In Additional Tissuesmentioning

confidence: 99%

miR-144/451 in hematopoiesis and beyond

Wang

2019

ExRNA

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MicroRNAs (miRNAs), a class of 18-25 nucleotide (nt) non-coding RNAs, usually inhibit the expression of their target genes. They are transcribed from endogenous genes and are processed for maturation by multiple pathways. miR-144/451, a bicistronic gene locus, encodes miR-144 and miR-451, both of which are highly conserved in evolution. These two miRNAs are on the same primary RNA molecule whose transcription is controlled by multiple nuclear proteins, including GATA1, GATA4, Myc, Oct1, Pax4, FXR, AP1, SMAD3 and SMAD4 depending on tissue types. They are abundant and almost exclusively exist in red blood cells, but low expression of both miR-144 and miR-451 are also detected in non-erythroid lineages. Interestingly, deletion of both miR-144 and miR-451 DNA sequences coding pre-miR-144/451 hairpins in mice leads only mild microcytic anemia but worsen upon a number of stresses including developmental stress, acute blood loss, phenohydrazine-induced hemolysis and precursor depletion by chemotherapeutic drug 5-FU. Such knockout animals older than 15 months also spontaneously develop malignant tumors including B-lymphoma and acute myeloid leukemia, indicating that miR-144/451 is a bona fide tumor-suppressing gene in non-erythroid cells, though its levels are much lower compared to that in red blood cells. Consistent with the findings in animals, disruption of miR-144/451 expression and their abnormal functions are observed in human hematopoietic and non-hematopoietic organs. Moreover, miR-451 is the only miRNA discovered so far whose maturation does not depend on Dicer, an enzyme required by all other miRNAs for maturation. This review focuses on the biogenesis, transcriptional regulation and biological roles of miR-144/451 in erythropoiesis, tumor initiation and other pathological conditions.

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“…Most work examining behavioural effects of amygdalar miRNA focuses on fear learning (Volk et al ., ). For example, inhibiting miR‐34a in the basolateral amygdala inhibits cued fear learning by disinhibiting Notch1 signalling (Dias et al ., ), although overexpressing amygdalar miR‐144‐3p (which also targets Notch1) enhances fear extinction (Murphy et al ., ). While a picture of the role of amygdalar miRNAs in mediating behavioural changes in response to environmental stimuli (i.e.…”

Section: Introductionmentioning

confidence: 97%

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

Cohen

Jackson

Ballestas

et al. 2017

Eur J of Neuroscience

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A greater understanding of neural mechanisms that contribute to anxiety is needed in order to develop better therapeutic interventions. The current study interrogates a novel molecular mechanism that shapes anxiety-like behavior, demonstrating that the microRNA miR-101a-3p and its target, enhancer of zeste homolog 2 (Ezh2) in the amygdala, contribute to rodent anxiety-like behavior. We utilized rats that were selectively-bred for differences in emotionality and stress reactivity, showing that high novelty responding (HR) rats, which display low trait anxiety, have lower miR-101a-3p levels in the amygdala compared to low novelty responding (LR) rats that characteristically display high trait anxiety. To determine if there is a causal relationship between amygdalar miR-101a-3p and anxiety behavior, we used a viral approach to over-express miR-101a-3p in the amygdala of HR rats and test whether it would increase their typically low levels of anxiety-like behavior. We found that increasing miR-101a-3p in the amygdala increased HRs’ anxiety-like behavior in the open field test and elevated plus maze. Viral-mediated miR-101a-3p over-expression also reduced expression of the histone methyltransferase Ezh2, which mediates gene silencing via tri-methylation of histone 3 at lysine 27 (H3K27me3). Knockdown of Ezh2 with short-interfering RNA (siRNA) also increased HRs’ anxiety-like behavior, but to a lesser degree than miR-101a-3p over-expression. Overall our data demonstrate that increasing miR-101a-3p expression in the amygdala increases anxiety-like behavior and that this effect is at least partially mediated via repression of Ezh2. This work adds to the growing body of evidence implicating miRNAs and epigenetic regulation as molecular mediators of anxiety behavior.

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MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice

Abstract: 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.

Cited by 62 publications

References 55 publications

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts

Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts

miR-144/451 in hematopoiesis and beyond

Amygdalar expression of the microRNA miR‐101a and its target Ezh2 contribute to rodent anxiety‐like behaviour

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