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 CO2 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 CO2-evoked behavioral and physiological responses in mice. We also investigated the role of TDAG8 in regulating CO2 inhalation-evoked fear-relevant behaviors and hyperventilation, as well as microglial morphology following CO2 inhalation in female mice. We found CO2 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 CO2 inhalation in females. However, TDAG8 deletion significantly attenuated CO2-evoked hyperventilation in females. Previous work in male mice showed CO2 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 CO2 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 CO2 inhalation, though effects on SFO microglia are consistent. Together these data highlight important sex differences in behavioral and physiological responses to panicogen, CO2 inhalation. They also highlight the need to consider phenotypic differences when exploring molecular mechanisms and circuitry driving panic-relevant outcomes in males and females.