Travis D. Goode

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 when 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.

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.