Oxytocin receptors in the dorsolateral bed nucleus of the stria terminalis (BNST) bias fear learning toward temporally predictable cued fear

Abstract

The inability to discriminate between threat and safety is a hallmark of stress-induced psychiatric disorders, including post-traumatic stress disorder. Dorsolateral bed nucleus of the stria terminalis (BNST dl ) is critically involved in the modulation of fear and anxiety, and has been proposed to regulate discrimination between signaled (cued, predictable) and unsignaled (unpredictable) threats. We recently showed that oxytocin receptors (OTRs) in the BNST dl facilitate acquisition of cued fear measured in a fear-potentiated startle (FPS). In the current study, using in vivo microdialysis in awake male Sprague–Dawley rats, a double immunofluorescence approach with confocal microscopy, as well as retrograde tracing of hypothalamic BNST-projecting OT neurons, we investigated whether fear conditioning activates OT system and modulates OT release. To determine the role of OTR in fear memory formation, we also infused OTR antagonist or OT into the BNST dl before fear conditioning and measured rats’ ability to discriminate between cued (signaled) and non-cued (unsignaled) fear using FPS. In contrast to acute stress (exposure to forced swim stress or foot shocks alone), cued fear conditioning increases OT content in BNST dl microdialysates. In addition, fear conditioning induces moderate activation of OT neurons in the paraventricular nucleus of the hypothalamus and robust activation in the supraoptic and accessory nuclei of the hypothalamus. Application of OT into the BNST dl facilitates fear learning toward signaled, predictable threats, whereas blocking OTR attenuates this effect. We conclude that OTR neurotransmission in the BNST dl plays a pivotal role in strengthening fear learning of temporally predictable, signaled threats.

Oxytocin Promotes Accurate Fear Discrimination and Adaptive Defensive Behaviors

“…These results indicate that OTR neurotransmission in the BNST DL facilitates the acquisition of fear to a discrete cue. We later confirmed the recruitment of endogenous OT in the acquisition of cued fear memory with a microdialysis study showing that cued-fear conditioning indeed evokes OT release in the BNST DL (Martinon et al, 2019).…”

“…We have recently shown that cued and contextual fear conditioning activate hypothalamic neurons differently, such that contextual fear conditioning (un-signaled foot-shocks) activates OT neurons in the PVN, SON, and AN, whereas cued fear conditioning (foot-shocks signaled by a cue) activates OT neurons in the SON and AN, but not the PVN of male rats. Overall, contextual fear conditioning caused more robust activation of OT neurons than cued fear conditioning in all three hypothalamic nuclei, suggesting that OT neurons are activated more in the conditions of uncertainty (Martinon et al, 2019). Previously, contextual fear conditioning was shown to activate magnocellular OT neurons in the PVN and SON of male rats (Zhu and Onaka, 2002).…”

“…Both cued fear and non-cued fear can be measured during FPS. Whereas cued fear is the startle potentiation measured during cue presentations, non-cued fear is measured as the startle potentiation observed in between the cue presentations (Missig et al, 2010;Ayers et al, 2011;Moaddab and Dabrowska, 2017;Janeček and Dabrowska, 2019;Martinon et al, 2019). However, as the latter response does not occur until after the cues are being presented, it can be used as a proxy of how well an animal discriminates between the presence and the absence of the cue.…”

“…After cued fear conditioning, fear discrimination can be defined as an ability to distinguish and primarily respond to cues predicting a learned aversive event versus cues that have no or little prognostic value of a threat (Janeček and Dabrowska, 2019;Martinon et al, 2019). The un-predictable or non-prognostic cues can be neutral (no association with either threat or safety) or they can signal safety.…”

“…In contrast to contextual fear regulation, surprisingly fewer studies have investigated the effects of OT on the modulation of cued fear (Toth et al, 2012;Moaddab and Dabrowska, 2017;Terburg et al, 2018;Martinon et al, 2019). No reported studies to date have investigated the role of OTRs in the modulation of cued fear in the CeA or LA, both critical for cued fear acquisition.…”