Abstract
<title>Abstract</title> <p>Interoception, the sensing and integration of internal bodily signals, is increasingly recognised as an important process in anxiety and panic disorders. Carbon dioxide (CO₂) inhalation provides a translational model of interoceptive threat by disrupting respiratory homeostasis through hypercapnia. However, it remains unclear how increasing CO₂ intensity shapes brain-wide neuronal activation associated with anxiety- and panic-like responses. To address this, we exposed mice to either 10% or 20%CO₂, with synthetic air serving as the control condition. Behavioural analysis revealed anxiety-like states during 10%CO₂ exposure and, in addition, panic-like responses during 20% CO₂ exposure accompanied by robust, concentration-dependent increases in corticosterone levels and pupil size, indicating acute activation of neuroendocrine stress pathways and autonomic arousal. Since behavioural regulation depends on coordinated activity across multiple brain regions, we performed a network analysis of c-Fos expression as a marker of neuronal activation. Inhalation of 10%CO₂ was associated with the densest and most globally coordinated pattern of c-Fos expression across brain regions. By contrast, 20% CO₂ exposure produced a more modular and fragmented network organization than 10%CO2, despite inducing marked increases in c-Fos density in brain areas implicated in threat-related processes including the locus coeruleus, nucleus tractus solitarius, dorsolateral bed nucleus of the stria terminalis, and paraventricular hypothalamic nucleus. Together, these findings suggest that increasing CO₂ concentrations elicit dissociable brain-wide c-Fos expression and putative functional co-activation profiles across interoceptive threat circuits, rather than simply reflecting a linear increase in neuronal activation, thereby supporting the presence of distinct neural signatures associated with anxiety- and panic-like states. </p>