ABSTRACT
Anxiety and trauma-related disorders are characterized by significant alterations in threat detection, resulting in inadequate fear responses evoked by weak threats or safety stimuli. Recent research pointed out the important role of the bed nucleus of stria terminalis (BNST) in threat anticipation and fear modulation under ambiguous threats, hence, exaggerated fear may be traced back to altered BNST function. To test this hypothesis, we chemogenetically inhibited specific BNST neuronal populations (corticotropin-releasing hormone - BNSTCRH and somatostatin - BNSTSST expressing neurons) in a predator odor-evoked innate fear paradigm. The rationale for this paradigm was threefold: (1) predatory cues are particularly strong danger signals for all vertebrate species evoking defensive responses on the flight-avoidance-freezing dimension (conservative mechanisms), (2) predator odor can be presented in a scalable manner (from weak to strong), and (3) higher-order processing of olfactory information including predatory odor stimuli is integrated by the BNST. Accordingly, we exposed adult male mice to low and high predatory threats presented by means of cat urine, or low- and high-dose of 2-methyl-2-thiazoline (2MT), a synthetic derivate of a fox anogenital product, which evoked low and high fear response, respectively. Then, we tested the impact of chemogenetic inhibition of BNSTCRH and BNSTSST neurons on innate fear responses using crh- and sst-ires-cre mouse lines. We observed that BNSTSST inhibition was effective only under low threat conditions, resulting in reduced avoidance and increased exploration of the odor source. In contrast, BNSTCRH inhibition had no impact on 2MT-evoked responses, but enhanced fear responses to cat odor, representing an even weaker threat stimulus. These findings support the notion that BNST is recruited by uncertain or remote, potential threats, and CRH and SST neurons orchestrate innate fear responses in complementary ways.
ABSTRACT
Excessive fear learning and generalized, extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in male mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear conditioning or memory consolidation resulted in enhanced cue-related fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cue-related fear recall subsequently, potentially via altered activity of downstream regions. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin (SOM), but not corticotropin-releasing factor (CRF), neurons of the BNST, which was accompanied by increased fear generalization. Our findings suggest the significant modulation of fear memory strength by specific circuits of the BNST.SIGNIFICANCE STATEMENT The bed nucleus of stria terminalis (BNST) mediates different defensive behaviors, and its connections implicate its integrative modulatory role in fear memory formation; however, the involvement of BNST in fear learning has yet to be elucidated in detail. Our data highlight that BNST stimulation enhances fear memory formation without direct effects on fear expression. Our study identified somatostatin (SOM) cells within the extended amygdala as specific neurons promoting fear memory formation. These data underline the importance of anxiety circuits in maladaptive fear memory formation, indicating elevated BNST activity as a potential vulnerability factor to anxiety and trauma-related disorders.
