Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety

Abstract

The lateral division of the bed nucleus of the stria terminalis (BNST), which forms part of the circuitry regulating fear and anxiety, contains a large number of neurons expressing corticotropin releasing factor (CRF), a neuropeptide that plays a prominent role in the etiology of fear- and anxiety-related psychopathologies. Stress increases CRF expression within BNST neurons, implicating these cells in stress- and anxiety-related behaviors. These experiments examined the effect of chronically enhanced CRF expression within BNST neurons on conditioned and unconditioned anxiety-related behavior by using a lentiviral vector containing a promoter that targets CRF gene over-expression (OE) to CRFergic cells. We found that BNST CRF over-expression did not affect unconditioned anxiety-like responses in the elevated plus maze or basal acoustic startle amplitude. CRF OE induced prior to training weakened sustained fear (conditioned anxiety); when induced after conditioning, CRF OE increased expression of the conditioned emotional memory. Increased BNST CRF expression did not affect plasma corticosterone concentration but did decrease CRFR1 receptor density within the BNST and CRFR2 receptor density within the dorsal portion of the caudal dorsal raphe nucleus. These data raise the possibility that the observed behavioral effects may be mediated by enhanced CRF receptor signaling or compensatory changes in CRF receptor density within these structures. Together, these studies demonstrate that CRF neurons within the lateral BNST modulate conditioned anxiety-like behaviors and also suggest that enhanced CRF expression within these neurons may contribute to inappropriate regulation of emotional memories.

Importance of CRF Receptor-Mediated Mechanisms of the Bed Nucleus of the Stria Terminalis in the Processing of Anxiety and Pain

“…Using specific CRF 1 and CRF 2 receptor antagonists, we found circumstantial evidence for both converging and opposing receptor functions, dependent on the behavior under investigation. Although our results support previous reports of CRF receptor function on the anxiety-like behavior in the EPM (Sahuque et al, 2006;Sink et al, 2013) and modulation of somatic pain processing (Ji and Neugebauer, 2008), the observed changes in visceral sensitivity contradicted previous studies using peripherally restricted CRF 1 and CRF 2 receptor antagonists (Greenwood- Nijsen et al, 2005). This suggested that the effects of CRF 1 and CRF 2 receptor activation, at least on visceral sensitivity, may differ depending on the localization of the receptors.…”

“…However, recent findings using similar CRF overexpression techniques in the BNST suggested that regulation of stress-induced anxiety in this brain region may depend more on the CRF receptors (Sink et al, 2013). Thus, our following experiments focused on delineating the function of the CRF receptors, which were disproportionally upregulated after WAS.…”

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…Moreover, Crh gene over-expression within the BNST increased the sustained fear response towards a previously conditioned fear cue 66 . Crh over-expression was followed by a decreased CRHR1 receptor density within the BNST suggesting that "behavioral effects may be mediated by enhanced CRH receptor signaling or compensatory changes in CRF receptor density within these structures" 66 .…”

“…Crh over-expression was followed by a decreased CRHR1 receptor density within the BNST suggesting that "behavioral effects may be mediated by enhanced CRH receptor signaling or compensatory changes in CRF receptor density within these structures" 66 . Importantly, CRH over-expression was impairing anxiety responses towards threat cues if administered prior to conditioning, and also, limbic CRHR1 was shown to be required for the enhancement of fear memory consolidation 8 .…”

The CRH1 Antagonist GSK561679 Increases Human Fear But Not Anxiety as Assessed by Startle

“…CRF 1 receptors also differentially affect these two aversive states in rodents (Refojo et al, 2011;Sink et al, 2013). In this species, sustained anxiety is maintained by activation of CRF 1 receptors and blocked by BNST infusion of CRH 1 antagonists (Davis et al, 2010;Lee and Davis, 1997), whereas fear is either not affected or even enhanced by CRF 1 antagonists (Meloni et al, 2006;Walker et al, 2009a, b).…”