MicroRNA-19b Associates with Ago2 in the Amygdala Following Chronic Stress and Regulates the Adrenergic Receptor Beta 1

Abstract

Activation of the stress response in the presence of diverse challenges requires numerous adaptive molecular and cellular changes. To identify specific microRNA molecules that are altered following chronic stress, mice were subjected to the chronic social defeat procedure. The amygdala from these mice was collected and a screen for microRNAs that were recruited to the RNA-induced silencing complex and differentially expressed between the stressed and unstressed mice was conducted. One of the microRNAs that were significantly altered was microRNA-19b (miR-19b). Bioinformatics analysis revealed the adrenergic receptor ␤-1 (Adrb1) as a potential target for this microRNA with multiple conserved seed sites. Consistent with its putative regulation by miR-19b, Adrb1 levels were reduced in the basolateral amygdala (BLA) following chronic stress. In vitro studies using luciferase assays showed a direct effect of miR-19b on Adrb1 levels, which were not evident when miR-19b seed sequences at the Adrb1 transcript were mutated. To assess the role of miR-19b in memory stabilization, previously attributed to BLA-Adrb1, we constructed lentiviruses designed to overexpress or knockdown miR-19b. Interestingly, adult mice injected bilaterally with miR-19b into the BLA showed lower freezing time relative to control in the cue fear conditioning test, and deregulation of noradrenergic circuits, consistent with downregulation of Adrb1 levels. Knockdown of endogenous BLA-miR-19b levels resulted in opposite behavioral and noradrenergic profile with higher freezing time and increase 3-methoxy-4-hydroxyphenylglycol/noradrenaline ratio. These findings suggest a key role for miR-19b in modulating behavioral responses to chronic stress and Adrb1 as an important target of miR-19b in stress-linked brain regions.

Pathogenetic and therapeutic applications of microRNAs in major depressive disorder

“…MiR-34c reduced the responsiveness of cells to CRF in neuronal cells endogenously expressing CRFR1. In basolateral amygdala of mice, Volk et al (2014) recently showed that miR-19b is modulated in response to social-defeat stress, which was associated with altered expression of adrenergic receptor β-1. Bilaterally injection with miR-19b into the this brain area showed lower freezing time relative to control in the cue fear conditioning test, and caused deregulation of noradrenergic circuits mediated through adrenergic receptor β-1.…”

Amygdalar MicroRNA-15a Is Essential for Coping with Chronic Stress

“…Recent studies have linked microRNA (miRNA) expression or biogenesis dysregulation to various psychiatric disorders, including anxiety and depression (Dias et al., 2014b, Issler and Chen, 2015, Issler et al., 2014, Lopez et al., 2014, O’Connor et al., 2012, Volk et al., 2014). However, changes in miRNA expression levels do not necessarily reflect their immediate activity; it is only when a specific miRNA, in the canonical pathway, has matured and been incorporated into the RNA-induced silencing complex (RISC) in the presence of argonaute RISC catalytic component 2 (Ago2) that it becomes truly active (Meister et al., 2004) as a result of its association with its target mRNA.…”

“…miR-34c is involved in regulating stress-induced anxiety (Haramati et al., 2011) and miR-34a in fear memory consolidation (Dias et al., 2014a). Furthermore, miR-19b plays an important role in memory consolidation following stress by regulating the adrenergic receptor beta 1 (Volk et al., 2014). …”

microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

“…Interestingly, a precursor miRNA family, mir-19b, has been implicated in PTSD [20,21] and is differentially expressed between SS and SR mice in our own laboratory. This same miRNA is enhanced in the amygdala following chronic social defeat stress and mir-19b in vivo manipulation bidirectionally modulated cued fear conditioning without altering contextual fear memory or anxiety-like behavior in the OFT, dark/light transfer test, or the EPM [14]. Further study of miRNAs altered by stress, such as mir-19b or mir-598-3p, which specifically influence amygdala-dependent memory without altering general anxiety-like behavior, may provide further insight into mechanisms contributing to PTSD.…”

“…We have previously shown that cued fear conditioning downregulates miR-182 in the lateral amygdala and that overexpression of miR-182 in this region during training disrupted expression of the fear memory the following day [12]. While these reports and others provide evidence that miRNAs can influence memory formation [13][14][15], studies to date have not addressed their impact on remote memory.…”