The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear

Abstract

While learning to fear stimuli that predict danger promotes survival, the inability to inhibit fear to inappropriate cues leads to a pernicious cycle of avoidance behaviors. Previous studies have revealed large inter-individual variations in fear responding with clinically anxious humans exhibiting a tendency to generalize learned fear to safe stimuli or situations. To shed light on the origin of these inter-individual variations, we subjected rats to a differential auditory fear conditioning paradigm in which one conditioned auditory stimulus (CS+) was paired to footshocks whereas a second (CS-) was not. We compared the behavior of rats that received pretraining excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) to that of sham rats. Sham rats exhibit a continuum of anxious/fearful behaviors. At one end of the continuum were rats that displayed a poor ability to discriminate between the CS+ and CS-, high contextual freezing, and an anxiety-like trait in the elevated plus maze (EPM). At the other end were rats that display less fear generalization to the CS-, lower freezing to context, and a nonanxious trait in the EPM. Although BNST-lesioned rats acquired similarly high levels of conditioned fear to the CS+, they froze less than sham rats to the CS-. In fact, BNST-lesioned rats behaved like sham rats with high discriminative abilities in that they exhibited low contextual fear and a nonanxious phenotype in the EPM. Overall, this suggests that inter-individual variations in fear generalization and anxiety phenotype are determined by BNST influences on the amygdala and/or its targets.

Figure 1.

Differential auditory fear conditioning in sham versus BNST-lesioned rats. A, Experimental paradigm. B, NeuN immunoreactivity in coronal sections of sham (left) versus BNST-lesioned rats (right). C, Percentage time freezing (average ± SEM) in response to the CS+ (filled circles) and CS− (empty circles) during fear conditioning (left), during exposure to the training context without tones (middle), and during the recall test (right) in sham (n = 28; C1, black) versus BNST-lesioned (n = 18; C2, red) rats.

Figure 2.

BNST lesions abolish behavioral heterogeneity related to discrimination abilities. A, Percentage time freezing in response to the CS+ (filled circles) and CS− (empty circles) in individual sham (black; n = 28) versus BNST-lesioned (red; n = 18) rats during fear conditioning (left), during exposure to the training context without tones (middle), and during the recall test (right). Lines indicate averages. B, Frequency distribution of discrimination scores in sham (black) versus BNST-lesioned (red) rats. C, Comparison between BNST-lesioned rats (red; n = 18) and sham rats with high (black bars; n = 10) or low (white bars; n = 18) discrimination scores in percentage time freezing (left y-axis) to training context (Ctx) and to CS+ and CS− during the recall test, as well as time in closed arms of EPM (right y-axis). D, E, Discrimination score (y-axis) versus freezing to training context (x-axis, D) or time in closed arms (x-axis, E).