The Bed Nucleus of the Stria Terminalis Is Critical for Anxiety-Related Behavior Evoked by CO2 and Acidosis

Abstract

Carbon dioxide (CO 2 ) inhalation lowers brain pH and induces anxiety, fear, and panic responses in humans. In mice, CO 2 produces freezing and avoidance behavior that has been suggested to depend on the amygdala. However, a recent study in humans with bilateral amygdala lesions revealed that CO 2 can trigger fear and panic even in the absence of amygdalae, suggesting the importance of extraamygdalar brain structures. Because the bed nucleus of the stria terminalis (BNST) contributes to fear-and anxiety-related behaviors and expresses acid-sensing ion channel-1A (ASIC1A), we hypothesized that the BNST plays an important role in CO 2 -evoked fear-related behaviors in mice. We found that BNST lesions decreased both CO 2 -evoked freezing and CO 2 -conditioned place avoidance. In addition, we found that CO 2 inhalation caused BNST acidosis and that acidosis was sufficient to depolarize BNST neurons and induce freezing behavior; both responses depended on ASIC1A. Finally, disrupting Asic1a specifically in the BNST reduced CO 2 -evoked freezing, whereas virus-vector-mediated expression of ASIC1A in the BNST of Asic1a Ϫ/Ϫ and Asic1a ϩ/ϩ mice increased CO 2 -evoked freezing. Together, these findings identify the BNST as an extra-amygdalar fear circuit structure important in CO 2 -evoked fear-related behavior.

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

“…Disrupting the asic1a gene in mice decreases acidosis-induced fear behavior, which can be restored through transgenic expression of asic1a in the amygdala (Ziemann et al, 2009). Similar findings have been reported for asic1a at the level of the bed nucleus of the stria terminalis (Taugher et al, 2014). We previously reported evidence of linkage between PD and a region of chromosome 12q encompassing the human ortholog of asic1a (ACCN2) (Smoller et al, 2001).…”

Two aspects of ASIC function: Synaptic plasticity and neuronal injury

“…Viral-mediated expression of ASIC1a in the ASIC1a null mice in amygdala rescues conditioned but not unconditioned fear (Coryell et al, 2008). In another study, site-specific deletion of ASIC1a in BNST is sufficient to abolish CO 2 -induced freezing (Taugher et al, 2014). These data indicate that ASICs in different structures have differential effects on fear induced by specific modality.…”

Neural Control of Breathing and CO2 Homeostasis

“…CO 2 -induced arousal protects against accidental asphyxia by enabling postural changes that alleviate airway obstruction. Arousal, negative emotions and, in rodents olfactory sensation, can, in turn, stimulate breathing and contribute to the ventilatory response to CO 2 (Hu et al, 2007; Kaur et al, 2013; Taugher et al, 2014). …”

“…Interpreting effects of brain lesions on the chemoreflex is also problematic (reviewed in (Guyenet, 2014; Nattie, 2011)). In such experiments, the chemoreflex is measured by exposing animals acutely to CO 2 levels that produce arousal and elicit behavioral effects (Kaur et al, 2013; Taugher et al, 2014). The effective lesions could have reduced ventilatory responses by any of three mechanisms: the lesioned neurons could indeed be respiratory chemoreceptors, they could mediate the emotional, behavioral or arousal effects of hypercapnia (Kaur et al, 2013; Taugher et al, 2014) or they could simply bias the chemoreflexes at multiple brain sites.…”