Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

Abstract

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.

Oxytocin Promotes Accurate Fear Discrimination and Adaptive Defensive Behaviors

“…In contrast to the CeA, which has been shown to mediate fear responses to short, discrete cues (cued fear), the BNST primarily mediates anxiety-like responses, as well as fear responses to unpredictable, diffuse, or un-signaled threats (Walker and Davis, 2008;Davis et al, 2010;Goode et al, 2019). The BNST might also inhibit cued fear (Meloni, 2006).…”

“…The un-predictable or non-prognostic cues can be neutral (no association with either threat or safety) or they can signal safety. Fear discrimination can be also defined as an ability to discriminate between signaled vs un-signaled threats (signal or cue predicts threat, whereas lack of signal represents threat apprehension) (Overmier et al, 1971;Goode et al, 2019). Accurate fear discrimination during confrontation with an immediate threat or threat-predicting cue is an adaptive response which promotes survival.…”

“…The BLA sends excitatory inputs also to the BNST (Gungor and Pare, 2016) and growing evidence suggests that the BNST plays a major role in the modulation of fear discrimination (Duvarci et al, 2009;Goode et al, 2019Goode et al, , 2020Janeček and Dabrowska, 2019;Martinon et al, 2019). Male rats with BNST lesions were trained in a discriminatory auditory fear conditioning paradigm (paired CS+ vs un-paired CS−) and showed significantly improved fear discrimination during fear recall test, such that they responded primarily to the CS+ while showing significantly reduced responses to CS− (Duvarci et al, 2009).…”

Reducing shock imminence eliminates poor avoidance in rats

“…In the second, WS-US contingency was varied to test how US certainty affects AR learning. In Pavlovian studies, reducing US imminence or certainty appears to promote anxiety over fear; freezing reactions are diminished and more flexible antipredator strategies increase (Rescorla 1968;Helmstetter and Fanselow 1993;Cain et al 2005;Waddell et al 2006;Mobbs et al 2007;Kim and Jung 2018;Goode et al 2019). Lesions that impair freezing rescue ARs in poor avoiders, suggesting that freezing reactions interfere with avoidance (Choi et al 2010;Lazaro-Munoz et al 2010;Moscarello and LeDoux 2013).…”

New Frontiers in Anxiety Research: The Translational Potential of the Bed Nucleus of the Stria Terminalis

“…In further support of these distinct functional roles, studies in rodents show that lesioning the amygdala eliminates conditioned fear to auditory (13) and visual conditioned stimuli (14) and reduces fear-potentiated startle (15), but does not alter anxiety-like behavior in an elevated plus maze (15) or anxiety-like responses to bright light or corticotropin-releasing hormone (CRH) injection (14). Conversely, lesioning the BNST attenuates anxiety-like responses (16–20) and alters cortisol release (21) but, importantly, does not affect conditioned fear (14, 17, 19, 20).…”