β-adrenergic receptor (β-AR) and corticotropin-releasing factor (CRF) regulation of excitatory glutamatergic neurotransmission in the Bed Nucleus of the Stria Terminalis (BNST) is critical for many stress-related behaviors. While β-AR/CRF interactions are well-documented in the dorsal BNST, few studies have examined this interaction in the ventral BNST (vBNST), the subregion with the highest abundance of norepinephrine (NE) inputs. We hypothesized that the extensive NE innervation of the vBNST may result in distinct mechanisms of β-AR/CRF interactions regulating glutamate transmission that may be relevant for stress-related behaviors. To test this hypothesis, we used electrophysiological, behavioral, and pharmacological approaches in stress-naïve and stress-exposed wild-type and transgenic mice. We found that in stress-naïve mice, β1-ARs drive vBNST glutamatergic transmission, whereas β2-ARs are required to enhance vBNST glutamate transmission in mice after acute stress. Both mechanisms require CRF signaling. Confirmed by in situ hybridization, these data indicate a novel mechanism whereby acute stress upregulates β2-ARs in CRF neurons to drive vBNST excitability. To assess the behavioral relevance of this mechanism, mice were tested for stress avoidance behavior in a novel combinatorial stress exposure model, where we found that only mice exposed to two simultaneous stressors within a single stress-exposure session showed long-term place avoidance behavior at 1, 7, and 28 days later. This effect was lost in mice with knockdown of β2-AR expression in CRF cells or in wild-type mice treated with a β2-AR antagonist after stress exposure. Taken together, our findings reveal a novel mechanism by which stress uncovers latent β2-AR/CRF enhancement of vBNST excitatory neurotransmission to induce long-term stress avoidance behavior.
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