Chronic Stress Induces Maladaptive Behaviors by Activating Corticotropin-Releasing Hormone Signaling in the Mouse Oval Bed Nucleus of the Stria Terminalis

Abstract

The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K ϩ current that stabilizes membrane potential) in ex vivo slices. CVMS also increased c-fos ϩ cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH ϩ and pituitary adenylate cyclase-activating polypeptide ϩ (PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase ϩ (a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors.

Early-life stress alters affective behaviors in adult mice through persistent activation of CRH-BDNF signaling in the oval bed nucleus of the stria terminalis

“…One possible cause could be a disrupted BNST neuronal circuitry. We and others found that acute optogenetic stimulation of the adult ovBNST increases maladaptive avoidance behaviors 20,21 . The BNST is an important node in the limbic forebrain stress-response circuitry that transmits stress information from structures such as the amygdala and hippocampus to the PVN and thereby participates in regulation of HPA axis responsivity 16 .…”

“…BNST CRH neurons, likely through indirect innervation of hypothalamic PVN neurons 16 , are also thought to modulate stress responses [17][18][19] . We and others have reported that optogenetic stimulation of the ovBNST is sufficient to induce avoidance behaviors 20,21 . We also found that ovBNST CRH dysfunction mediates chronic stressinduced avoidance behaviors in adult mice 21 .…”

“…We and others have reported that optogenetic stimulation of the ovBNST is sufficient to induce avoidance behaviors 20,21 . We also found that ovBNST CRH dysfunction mediates chronic stressinduced avoidance behaviors in adult mice 21 . Although ELS affects CRH and induces persistent developmental alterations in the hypothalamus and other areas [22][23][24][25] , remarkably little is known about how ELS modulates CRH signaling in BNST.…”

“…Standard whole-cell voltage-clamp patch recording was performed as previously described 21,47,48 Recordings were performed using glass pipettes pulled with a PC-10 Puller (Narishige, Japan). Axopatch 200B amplifier, Digidata 1322 A Data Acquisition System, and pCLAMP software (version 10.2; Molecular Devices, Sunnyvale, CA) were used for data acquisition and analysis.…”

“…Local cannula drug infusion into the ovBNST MS or Control mice (n = 8 per group) were bilaterally implanted with a guide cannula (C315G/SPC, Plastics One, VA) directly into the ovBNST (bregma AP + 0.2 mm, ML 1.0 mm, DV −4.1 mm). After a 1 week recovery period, R121919 (1 μg in 0.5 μl saline) 53 , with or without the protein kinase A (PKA)-selective agonist forskolin 21 (120 nM in 0.5 μl saline), was continuously infused at 0.05 μl/min into ovBNST for 7 days. Another group of MS mice (n = 7) was infused with R1219191 (1 μg in 0.5 μl saline) together with BDNF (0.375 μg in 0.5 μl saline) 54 into ovBNST for 7 days.…”