Sex differences in responses to panicogen CO2 inhalation and the role of microglial acid-sensor TDAG8 in female mice

Prior work found microglial acid-sensor T-cell death-associated gene 8 (TDAG8) mediates panic-relevant responses to interoceptive stressor CO 2 inhalation in male mice. Yet panic disorder is more common in women and panic attack symptoms vary in men and women. Here, we investigated sex differences in CO 2 -evoked behavioral and physiological responses in mice. We also investigated the role of TDAG8 in regulating CO 2 inhalation-evoked fear-relevant behaviors and hyperventilation, as well as microglial morphology following CO 2 inhalation in female mice. We found CO 2 inhalation evoked greater fear-relevant behaviors and hyperventilation in female compared to male mice. Contrary to prior findings in males, we found TDAG8 deletion did not affect fear-relevant defensive responses to CO 2 inhalation in females. However, TDAG8 deletion significantly attenuated CO 2 -evoked hyperventilation in females. Previous work in male mice showed CO 2 inhalation induces morphological indicators of microglial activation within circumventricular organ the subfornical organ (SFO) in a TDAG8-dependent manner. Consistent with males, TDAG8 deletion in females attenuated morphological indicators of microglial activation following CO 2 inhalation within the SFO, but not within another TDAG8-expressing circumventricular organ, the organ vasculosum of the lamina terminalis (OVLT). This suggests a divergence in the role of TDAG8 in mediating behavioral versus physiological responses to panicogen CO 2 inhalation, though effects on SFO microglia are consistent. Together these data highlight important sex differences in behavioral and physiological responses to panicogen, CO 2 inhalation. They also highlight the need to consider phenotypic differences when exploring molecular mechanisms and circuitry driving panic-relevant outcomes in males and females.