Progestin infusion into the hypothalamus of CO₂-chemoreflex impaired female rats enhances the hypercapnic ventilatory response

The central CO 2 -chemoreflex, driven mainly by the retrotrapezoid nucleus (RTN), provides respiratory drive during homeostatic challenges. Additional brain structures also contribute to the CO 2 response, although their exact contribution remains unresolved. Progesterone and its synthetic derivatives can enhance chemoreflexes. We previously reported that systemic administration of the progestinic drug, etonogestrel (ETO), ‘rescued’ the CO 2 -chemoreflex following RTN lesion in female rats. However, similar effects were not observed in males. Given this sex-specific recovery, we surmised that ETO acts on the hypothalamus, a structure exhibiting sexual dimorphism. Specifically, the dorsomedial hypothalamus (DMH) projects to respiratory-related nuclei and expresses progesterone receptors. We hypothesized that ETO infusion into the DMH would elicit CO 2 -chemoreflex recovery similar to that observed in systemically treated female rats. To test this, the CO 2 -chemoreflex was impaired in adult female Sprague-Dawley rats by lesioning RTN neurons with substance P-conjugated saporin toxin. Rats were then instrumented with bilateral cannulae + osmotic pumps containing ETO (0.056 ng/μL) or vehicle delivering the drug into the DMH for 4 weeks. Respiration in room air, hypercapnia and hypoxia was measured using whole-body plethysmography. Fixed brains were collected to determine cannula placement, lesion quantification and cFOS expression analyses. Preliminary data suggest that ETO induced modest CO 2 -chemoreflex recovery in rats with moderate-sized RTN lesion by increasing tidal volume and breathing frequency, while hypoxic ventilation was unaffected. In rats with large RTN lesion, no restorative effect was observed. These data suggest a potential ETO-induced compensatory role for DMH neurons following central CO 2 -chemoreflex impairment but do not rule out contributions from other brainstem nuclei based on previous systemic ETO administration. T.A.J.: CLA BaO Fellowship, CIHR Fellowship. A.S.P.S.: Studentships from WCHRI and NSERC. S.C.: CLA BaO Fellowship. S.P.: WCHRI Innovation Grant, CIHR Project Scheme Grant This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.