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

Abstract

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.

Lentiviral-mediated let-7d microRNA overexpression induced anxiolytic- and anti-depressant-like behaviors and impaired dopamine D3 receptor expression

“…The overexpression of other miRNAs such as miR-17-92, miR-34b also decreased anxiety-like behavior in mice and rats respectively ( Jin et al, 2016;Zhu et al, 2017 ). However, miR-101a-3p-overexpressing adeno-associated viruses (AAVs) in the amygdala increased anxiety-like behavior in the OF and EPM tests of high-novelty-responding (HR) rats ( Cohen et al, 2017 ). Also, miR-155 KO mice exhibited reduced float duration and increased latency to float ( Fonken et al, 2016 ), but, no changes in anxiety-like behavior were observed in miR-132/212 KO mice ( Hernandez-Rapp et al, 2015 ).…”

MiR‐101a ameliorates AngII‐mediated hypertensive nephropathy by blockade of TGFβ/Smad3 and NF‐κB signalling in a mouse model of hypertension

“…Hence, the above findings suggest that miR‐101a could be a potential diagnostic factor and therapeutic target for hypertensive kidney disease. On the other hand, some other targets of miR‐101a have been previously reported, such as Ezh2 in anxiety behaviour, fosab in zebrafish heart regeneration and so on. However, whether these above miR‐101a's targets are also involved in hypertensive nephropathy needs to be further analyzed.…”

Multiple miRNAs jointly regulate the biosynthesis of ecdysteroid in the holometabolous insects, Chilo suppressalis

“…It should be noticed that 1351 miRNAs were from 12 Drosophila species, which accounted for about half of known insect miRNAs (Kozomara and Griffiths-Jones 2014). Many studies to elucidate the functions of miRNAs in regulating a variety of insect physiological processes have been carried out, such as in metamorphosis development (Sokol et al 2008;Gomez-Orte and Belles 2009;Ling et al 2014;Belles 2017;Wu et al 2017), cell growth (Wang et al 2010), behavior (Cohen et al 2017), sex determination (McJunkin and Ambros 2017), oogenesis , embryogenesis (Jannot et al 2016), immunity (Zhu et al 2013), insect-pathogen interactions (Hussain and Asgari 2010;Asgari 2013;Wu et al 2016), etc. Several miRNAs have been reported to regulate insect metamorphosis by targeting genes either in the ecdysone cascade or the JH cascade (Zhang et al 2009;Belles 2017).…”