BEHAVIOURAL HYPERSENSITIVITY TO CARBON DIOXIDE (CO<SUB>2</SUB>) IS ASSOCIATED WITH ALTERED PROCESSING OF INTEROCEPTIVE THREAT IN HIGH-TRAIT-ANXIETY MICE

Individuals diagnosed with anxiety disorders often show disrupted perception of internal bodily signals. Although altered interoception is recognized as an important component of anxiety disorders, its underlying neural mechanisms remain insufficiently characterized. Here, we aimed to determine whether trait anxiety levels influence the recruitment of anxiety-related brain circuits during CO₂ exposure, a well-established translational model for probing interoception-driven negative valence. Mice with high (HAB) and normal (NAB) trait anxiety-related behavior were exposed to 10% CO₂‑enriched air while behavioral and physiological responses were recorded. CO₂ exposure was anxiogenic in both lines with greater behavioral and autonomic effects in HAB mice. c‑FOs expression, as marker of neuronal activation, revealed hyperactivity of several limbic, hypothalamic, and brainstem regions known to be involved in stress- and/or anxiety processing in HAB compared with NAB mice, independent of experimental condition. Notably, CO₂ exposure activated the paraventricular nucleus of the hypothalamus in both lines, with a significantly stronger response in HAB mice. In HABs, CO₂ inhalation increased c-Fos–positive cells selectively in the lateral amygdala, whereas no increase was observed in basal amygdalar or insular subregions. In contrast, NABs exhibited increased c-Fos expression in these regions following CO₂ exposure. Collectively, these findings suggest that high trait anxiety is associated with altered CO₂ sensitivity, mirroring features of anxiety disorders, and dysregulated engagement of classical stress-related and interoceptive threat-processing circuits. Thus, HAB mice represent a valid model for studying the neurobiological basis of interoception-triggered hypersensitivity in high trait anxiety.

Supported by the Austrian Science Fund FWF FG18-B.