Sex differences in central salt sensing in the human brain

In preclinical models, the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) sense changes in serum sodium chloride (NaCl) concentration and mediate NaCl-induced changes in sympathetic nerve activity, vasopressin (AVP), thirst, and blood pressure (BP). In humans, brain imaging studies have shown that acute hypernatremia alters the activity or functional connectivity of the SFO and OVLT. However, no studies have investigated whether there are sex differences in central NaCl sensing in humans, which could underlie sex differences in neurohumoral responses to hypernatremia. Therefore, the purpose of this study was to test the hypothesis that acute relative hypernatremia would increase resting-state functional connectivity between NaCl-sensing brain regions and that these responses would be greater in men. Thirty-two young adults (17 men/15 women) underwent resting-state functional magnetic resonance imaging (fMRI) at baseline and during a 30-minute intravenous hypertonic saline infusion. We performed a seed-to-seed functional connectivity analysis. Despite similar increases in serum sodium, thirst, systolic BP, and plasma AVP between the sexes, there was a time*sex interaction (p<0.001) on SFO-OVLT functional connectivity, as SFO-OVLT functional connectivity increased in men during the late phase (15-30 minutes) of the hypertonic saline infusion (z-scores: baseline=0.21±0.20, late phase=0.29±0.21; p=0.04), but decreased in women (z-scores: baseline=0.27±0.17, late phase=0.15±0.18; p=0.004). Collectively, these results suggest that the functional coupling of the SFO and OVLT, which regulate sympathoexcitation and BP during acute hypernatremia, may be modulated by sex.