MicroRNA-19b associates with Ago2 in the amygdala following chronic stress and regulates the adrenergic receptor beta 1.
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 β-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.
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany, and.
Naama
N
Volk
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany, and Department of Integrative Physiology, University of Colorado Boulder, Boulder, 80309 Colorado.
Evan D
ED
Paul
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Sharon
S
Haramati
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Chen
C
Eitan
Department of Integrative Physiology, University of Colorado Boulder, Boulder, 80309 Colorado.
Brandon K K
BKK
Fields
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Raaya
R
Zwang
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Shosh
S
Gil
Department of Integrative Physiology, University of Colorado Boulder, Boulder, 80309 Colorado.
Christopher A
CA
Lowry
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany, and alon.chen@weizmann.ac.il.
Alon
A
Chen
D000679:Amygdala / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D003214:Conditioning, Classical; D046352:Freezing Reaction, Cataleptic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
C547788:Adrb1 protein, mouse; C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; C561642:MIRN19 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1
Ago2; adrenergic receptor beta 1; amygdala; microRNA; stress