Role of the bed nucleus of the stria terminalis in aversive learning and memory

Abstract

Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective forebrain"-including the amygdala, ventral hippocampus, and medial prefrontal cortex-and the hypothalamic and brainstem areas that have been implicated in neuroendocrine, autonomic, and behavioral responses to actual or anticipated threats. However, the precise contribution of the BNST to defensive behavior is unclear, both in terms of the antecedent stimuli that mobilize BNST activity and the consequent defensive reactions. For example, it is well known that the BNST is essential for contextual fear conditioning, but dispensable for fear conditioning to discrete conditioned stimuli (CSs), at least as indexed by freezing behavior. However, recent evidence suggests that there are circumstances in which contextual freezing may persist independent of the BNST. Furthermore, the BNST is involved in the reinstatement (or relapse) of conditioned freezing to extinguished discrete CSs. As such, there are critical gaps in understanding how the BNST contributes to fundamental processes involved in Pavlovian fear conditioning. Here, we attempt to provide an integrative account of BNST function in fear conditioning. We discuss distinctions between unconditioned stress and conditioned fear and the role of BNST circuits in organizing behaviors associated with these states. We propose that the BNST mediates conditioned defensive responses-not based on the modality or duration of the antecedent threat or the duration of the behavioral response to the threat-but rather as consequence the ability of an antecedent stimulus to predict when an aversive outcome will occur (i.e., its temporal predictability). We argue that the BNST is not uniquely mobilized by sustained threats or uniquely involved in organizing sustained fear responses. In contrast, we argue that the BNST is involved in organizing fear responses to stimuli that poorly predict danger will occur, no matter the duration, modality, or complexity of those stimuli. The concepts discussed in this review are critical to understanding the contribution of the human BNST to fear and anxiety disorders.

Intrinsic functional connectivity of the central extended amygdala

“…Converging lines of anatomical, mechanistic, and physiological evidence make it clear that the central extended amygdala (EAc) is a key hub in this circuitry (Figure a,b) (Avery, Clauss, & Blackford, ; Davis, Walker, Miles, & Grillon, ; Fox & Shackman, in press; Goode & Maren, ; Gungor & Paré, ; Shackman & Fox, ; Tovote, Fadok, & Luthi, ). The EAc encompasses a collection of subcortical regions with similar cellular compositions, neurochemistry, gene expression, and structural connectivity and it encompasses the bed nucleus of the stria terminalis (BST), the central nucleus of the amygdala (Ce), the sublenticular extended amygdala (SLEA), and portions of the accumbens shell (Alheid & Heimer, ; Fox, Oler, Tromp, Fudge, & Kalin, a; Oler et al, ; Yilmazer‐Hanke, ).…”

Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies—potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST)

“…In line with the expanded model, we propose the BNST modulates ability to discriminate between cued (signaled, predictable, phasic) vs. non-cued (un-signaled, unpredictable, sustained) fear, for review see (Gungor and Pare, 2016; Goode and Maren, 2017). Lesioning BNST in rats significantly improved ability to discriminate between a cue paired with US (CS + ) vs. cue that has not been paired with US (CS − ).…”

“…Although initial lesion studies did not implicate the BNST in fear conditioning to short, discrete cues (LeDoux et al, 1988; Hitchcock and Davis, 1991; Gewirtz et al, 1998), growing evidence suggests that the BNST also modulates conditioned fear response to a discrete cue, for review see (Gungor and Pare, 2016; Goode and Maren, 2017). Specifically, the BNST appears to play a pivotal role in learning to accurately discriminate and differentially respond to stimuli representing threat and safety (Duvarci et al, 2009; De Bundel et al, 2016; Lange et al, 2017; Moaddab and Dabrowska, 2017).…”

“…Hence, as observed in infants, children, and adults, we are innately biased toward rapid detection of threatening vs. non-threatening stimuli (LoBue and DeLoache, 2008) and fearful vs. happy or neutral facial expressions (LoBue, 2009). In contrast to fear, anxiety occurs in the absence of a threat stimulus or in anticipation of a threat, and can be defined as a sustained and maladaptive response to diffuse, less specific, unpredictable or un-signaled threats (Davis et al, 2010; Goode and Maren, 2017). Anxiety can occur as an over-generalization of learned fear, inability to extinguish conditioned fear, and inability to discriminate between threat and safety (Lissek et al, 2014; Dunsmoor and Paz, 2015).…”

“…We support this interpretation by examining OTR transmission in dorsolateral BNST (BNST dl ), a critical brain structure that translates stress into anxiety (Davis et al, 2010; Dabrowska et al, 2013b; Sparta et al, 2013; Daniel and Rainnie, 2016). BNST dl has been proposed to play a pivotal role in the ability to discriminate between predictable vs. unpredictable stimuli (De Bundel et al, 2016), stimuli representing threat vs. safety (Duvarci et al, 2009), phasic vs. sustained fear responses (Walker et al, 2009a; Lange et al, 2017), and signaled vs. un-signaled threats; for review see (Gungor and Pare, 2016; Shackman and Fox, 2016; Goode and Maren, 2017). Based on our previously published data on OTR modulation of a fear-potentiated startle (FPS) (Moaddab and Dabrowska, 2017), we show that OTR facilitates discrimination between cued fear and background anxiety, such that endogenous OT biases rats’ responses toward predictable, signaled fear, but it reduces responses to un-signaled and un-predictable threats.…”