Sex Differences in Central Sodium Sensing in the Human Brain

Central sodium sensing is critical in mediating sodium-induced changes in vasopressin (AVP), sympathetic nerve activity, and blood pressure (BP) in preclinical models. In humans, acutely increasing serum sodium via a 3% NaCl intravenous (IV) infusion increases functional connectivity between the subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT), suggesting that these brain regions may sense serum sodium in humans. However, no studies have investigated sex differences in sodium sensing in the human brain, which may underly sex differences in BP regulation and fluid balance. Objective: To test the hypothesis that acute hypernatremia would increase functional connectivity between the SFO and OVLT to a greater extent in young men compared to young women. Methods: Thirty-two young healthy adults (age=27±4yr; 17 men/15 women) underwent functional magnetic resonance imaging at rest and during a 30-minute 3% NaCl IV infusion (0.15 ml/kg/min). Women were tested in the follicular menstrual cycle phase and not using hormonal contraception. Venous blood samples were obtained pre- and post-infusion to verify changes in serum sodium. A seed-to-seed functional connectivity analysis was performed to assess functional connectivity between the SFO and OVLT, which were 2mm-radius spheres. A 2x2 (sex*time) repeated measures ANOVA was used to assess changes in serum sodium pre- to post-infusion and changes in SFO-OVLT functional connectivity z-scores from baseline to the late phase (15-30 min) of the infusion. Associations between the day of the menstrual cycle that women were tested (range: day 2-11) and SFO-OVLT functional connectivity z-scores were assessed via Spearman’s correlations. Results: Serum sodium increased pre- to post-infusion (pre: 138.4±2.0 mmol/L, post: 141.5±1.8 mmol/L, n=30, p<0.001) with no sex differences (sex: p=0.661; sex*time: p=0.964). There was a significant sex*time interaction (p<0.001) for SFO-OVLT functional connectivity, such that functional connectivity increased in men with sodium loading (baseline: 0.21±0.20, late-phase: 0.29±0.21) but decreased in women (baseline: 0.27±0.17, late-phase: 0.15±0.18). In women, there were significant negative correlations between menstrual cycle day and SFO-OVLT functional connectivity at baseline (ρ=-0.550, p=0.036) and during the infusion’s late phase (ρ=-0.672, p=0.007), suggesting that women tested later in their menstrual cycle had lower SFO-OVLT functional connectivity. Conclusion: We identified sex differences in change in functional connectivity between the SFO and OVLT with sodium loading. Female sex hormones may also play a role as menstrual cycle day correlated with SFO-OVLT functional connectivity in women. Funding: R01HL163906, R21AG074544, F32HL158149, F31HL170563, P20GM113125 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.