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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
beta-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.
