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Sex differences in responses to panicogen CO2 inhalation and the role of microglial acid-sensor TDAG8 in female mice
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DOI：10.3389/fncel.2026.1865360.png)
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Abstract
En 中文
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.
Keywords:
microglia
sex differences
CO2 inhalation
panic disorder (PD)
TDAG8
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