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.IMPACT STATEMENTThe bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to unpredictable threats, a function that may be central to pathological anxiety.

Phasic signaling in the bed nucleus of the stria terminalis during fear learning predicts within- and across-session cued fear expression

“…Two subsequent decades of work have improved this perhaps oversimplified distinction between amygdala versus BNST mediating fear versus anxiety. The BNST has since been identified as an important mediator of the limbic forebrain processes that encode aversive motivational states, specifically ambiguous or temporally unpredictable aversive cues (Davis et al 2010, Daldrup et al 2016, Goode and Maren, 2017, Naaz et al 2019, Goode et al 2019).…”

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

“…Taken together, BNST did not affect acute fear responses (exhibited either during conditioning or recall), supporting that predictable CS-induced fear expression is not dependent on BNST activity (Goode et al, 2019;Sullivan et al, 2004). However, it had significant impact on fear memory formation that subsequently manifested in enhanced fear levels.…”

“…Early studies investigating the rodent BNST observed functional division between the amygdala and BNST, which was supported by human fMRI data. According to this model, amygdala mediates imminent phasic 'fear-like' states, whereas BNST mediates more diffuse unconditioned 'anxiety-like' states (Daniel and Rainnie, 2016;Davis et al, 2010;Goode et al, 2019). Recently, accumulating evidence showed that both amygdala and BNST are recruited under both phasic and sustained (or conditioned and unconditioned) fear-like states in humans and primates (Gungor and Paré, 2016;Shackman and Fox, 2016).…”

“…Recent models reconcile the controversies by emphasizing the dimensionality of fearful stimuli, i.e. the recruitment of BNST is gradiently increased by unpredictability (Goode and Maren, 2017;Goode et al, 2019;Gungor et al, 2016), and hence, it has a potential role in fear generalization (De Bundel et al, 2016;Duvarci et al, 2009).…”

Reducing shock imminence eliminates poor avoidance in rats

“…In the second, WS-US contingency was held constant, but WS duration was varied to test how US imminence affects AR learning. In Pavlovian studies, reducing US certainty or imminence appears to promote anxiety over fear; freezing reactions are diminished and more flexible antipredator strategies increase (Blanchard et al, 1989;Cain et al, 2005;Goode et al, 2019;Helmstetter and Fanselow, 1993;Kim and Jung, 2018;Mobbs et al, 2007;Rescorla, 1968;Waddell et al, 2006). Also, 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).…”