Stress Engages Novel Beta‐Adrenergic Receptor and CRF1 Receptor Mediated Glutamatergic Signaling in the Ventral Bed Nucleus of the Stria Terminalis

Abstract

Pathological stress reactivity is a critical factor in many mental health disorders. In order to better treat pathological stress‐related mental health disorders, a better understanding of the neurocircuitry governing homeostatic stress responses is needed. The bed nucleus of the stria terminalis (BNST) is a heterogenous limbic structure that plays a crucial role in the central nervous system's response to stress. During normal stress responding, norepinephrine signaling in the BNST is increased and modulates glutamatergic transmission. Prior experiments showed that stimulating beta1‐adrenergic receptors (β1‐ARs) enhances glutamatergic transmission in the dorsal lateral BNST (dBNST) through the modulation of corticotropin releasing factor (CRF) signaling. However, whether this mechanism is conserved in other subregions of the BNST has not been well‐studied. Therefore, this study sought to determine the mechanism by which β‐AR stimulation might modulate glutamatergic transmission in the ventral BNST (vBNST). Using whole‐cell patch clamp electrophysiology, spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from vBNST neurons in brain slices from adult male C57BL/6J mice. Mice were either exposed to one‐hour restraint stress or left as stress‐naïve prior to obtaining the slices. At baseline, sEPSC frequency was significantly higher in stressed than naïve mice (p<0.05). In both naïve and stressed mice, 10‐min bath application of the non‐selective β‐AR agonist, isoproterenol (3 μM), significantly increased vBNST sEPSC frequency (p<0.001). In both conditions, the isoproterenol effect was blocked by the selective β1‐AR antagonist betaxolol (10 μM), indicating that isoproterenol is acting through a β1‐AR mediated mechanism. The CRF1 receptor antagonist, NBI 27914 (1 μM), blocked the isoproterenol effect, indicating similar β1‐AR/CRF1 receptor circuit interactions in both the dorsal and ventral BNST. Surprisingly, although 10‐min application of the β2‐AR agonist clenbuterol (10 μM) did not change sEPSC frequency in naïve mice (p>0.05), clenbuterol did significantly increase sEPSC frequency in stressed mice (p<0.05). NBI 27914 blocked the clenbuterol effect in stressed mice, indicating a role for CRF1 receptors in this β2‐AR circuit. Additionally, using RNAscope in‐situ hybridization, expression of β2‐AR mRNA was upregulated following stress, specifically in CRF expressing neurons. These results suggest that stress induces de novo β2‐AR expression in vBNST CRF neurons that act to stimulate glutamate release within this brain region. These results uncover novel stress neurocircuitry in the vBNST and further investigation of this circuit may lead to possible therapeutic targets for treatment of chronic stress.Support or Funding InformationThis work funded by NIH grant AA22937.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.