β-arrestin-dependent ERK signaling positively correlates with reduced anxiety-like and conditioned fear-related behavior in mice

Exposure to anxiety- or fear-invoking stimuli initiates a convergence of executive actions orchestrated by multiple proteins and neurotransmitters across the brain. Dozens of G protein-coupled receptors (GPCRs) have been linked to regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but may also engage downstream kinases and effectors through {beta}-arrestin scaffolds. Here, we investigate whether {beta}-arrestin signaling can regulate anxiety-like and fear-related behavior. Using the {delta}-opioid receptor ({delta}OR) as a model GPCR, we found that {beta}-arrestin 2-dependent activation of extracellular signal-regulated kinases (ERK1/2) in the dorsal hippocampus and the amygdala are critical for {delta}OR agonist-induced anxiolytic-like effects. In contrast, G protein-mediated {delta}OR signaling was associated with decreased ERK1/2 activity and increased fear-related behavior. Our results also indicate unique contributions for {beta}-arrestin isoforms in modulation of anxiety-like and fear-related behavior. Overall, our findings highlight the significance of non-canonical {beta}-arrestin signaling in the regulation of emotions. One sentence summaryUsing pharmacological and genetic strategies, we reveal the importance of non-canonical {beta}-arrestin-mediated G protein-coupled receptor signaling in anxiety-like behaviors.