Corticotropin-Releasing Hormone Signaling in the Oval Bed Nucleus of the Stria Terminalis Mediates Chronic Stress-Induced Negative Valence Behaviors Associated with Anxiety

Abstract The bed nucleus of stria terminalis (BNST) is a forebrain region highly sensitive to stress that expresses corticotropin-releasing hormone (CRH) neuropeptide at high levels and regulates negative valence behaviors associated with anxiety. However, how chronic stress modulates CRH signaling and neuronal activity in BNST remains unknown. We subjected C57BL6/J mice to a 6-week chronic variable mild stress (CVMS) paradigm and investigated the effects on behavior, BNST cellular neurophysiology, and BNST CRH signaling. We also utilized pharmacological infusions and optogenetics to decipher and mimic the effects of CVMS on BNST cellular neurophysiology and behavior. CVMS elevated plasma corticosterone levels, induced negative valence behaviors associated with anxiety, diminished M-currents (voltage-gated K+ currents that stabilize membrane potential and regulate neuronal excitability), and increased mEPSC amplitude in ovBNST. Additionally, the number of c-fos+, CRH+, and CRH activator pituitary adenylate cyclase-activating polypeptide (PACAP)+ cells were increased while CRH inhibitor striatal-enriched protein tyrosine phosphatase (STEP)+ cells were decreased in ovBNST. These expression data were confirmed with qPCR. CVMS also activated PKA in BNST and the electrophysiological and behavioral effects of CVMS were reversed by ovBNST infusion of the PKA-selective antagonist H89. Moreover, optogenetic activation of ovBNST directly induced negative valence behaviors associated with anxiety, mimicking the effects of CVMS. CVMS mediates effects on negative valence behaviors associated with anxiety by activating CRH signaling components and cellular excitability in ovBNST Our findings decipher an important CRH-associated stress molecular signature in BNST and advance our understanding of the neural circuitry underlying stress-induced disorders.