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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.
Highlights
Excessive apprehension about potential future threats, including financial loss, illness, or death, is a defining feature of many anxiety disorders, including generalized anxiety disorder (GAD) (Behar et al, 2009)
Consistent with our hypothesis, we found that bed nucleus of the stria terminalis (BNST) inactivation reduced freezing to a BW, but not FW, CS
To determine whether the BNST is involved in other conditioning procedures imbued with outcome uncertainty, we examined whether freezing to a FW CS that is paired with a unconditioned stimulus (US) of variable intensity is BNST-dependent
Summary
Excessive apprehension about potential future threats, including financial loss, illness, or death, is a defining feature of many anxiety disorders, including generalized anxiety disorder (GAD) (Behar et al, 2009). We and others have proposed that the BNST may have a critical role in processing temporally unpredictable threats, in mediating defensive responses to threatening stimuli that poorly predict when an aversive event will occur (Goode and Maren, 2017; Lange et al, 2017; Luyck et al, 2018a) Consistent with this view, punctate auditory CSs that are followed by shock at unpredictable latencies yield freezing responses that are sensitive to BNST manipulations (Daldrup et al, 2016; Lange et al, 2017). These data reveal that BNST circuits process the expression of defensive behavior in the presence of unpredictable threat signals
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