Sex differences in central neural activation during acute hypernatremia

Abstract

Central salt sensing in the circumventricular organs (CVOs) is critical in regulating neurohormonal responses to acute relative hypernatremia as occurs with high dietary salt intake. The CVOs, including the organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), are capable of sensing changes in the salt concentration in the blood and mediate salt-induced changes in sympathetic nerve activity (SNA), vasopressin (AVP), thirst, and blood pressure (BP). Central salt sensing is also associated with the development of salt sensitive hypertension in rodents. Studies in humans demonstrate that acute relative hypernatremia alters the activity or functional connectivity of the CVOs. However, no studies have investigated whether there are sex differences in central neural activation during acute hypernatremia in humans, which could underly sex differences in neurohumoral responses to salt loading. Therefore, the purpose of this study was to investigate whether there are sex differences in the activation patterns of salt sensing and sympathoregulatory brain regions during acute hypernatremia. Thirty-two young healthy adults (17 men/15 women) underwent blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest and during a 30-minute intravenous (IV) hypertonic saline infusion (3% NaCl). Women were not using hormonal contraception and were tested during the follicular menstrual cycle phase. We calculated fractional amplitude of low frequency fluctuations (fALFF), which reflects the intensity of the spontaneous fluctuations in the BOLD signal in each brain region, and functional connectivity, which reflects the synchronization of low frequency fluctuations in the BOLD signal between our regions of interest. We hypothesized that acute hypernatremia would increase the fALFF in and functional connectivity between brain regions involved in sensing salt and increasing sympathetic outflow, while decreasing in nuclei that inhibit sympathetic outflow. We also hypothesized that these responses would be heightened in men. The main findings of this study were that acute relative hypernatremia increased fALFF in several brain regions associated with salt sensing and thirst, including the SFO, OVLT, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), insula, and thalamus, and in several sympathoregulatory brain regions, including the paraventricular nucleus (PVN), supraoptic nucleus (SON), rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), and caudal ventrolateral medulla (CVLM). Overall, changes in fALFF were similar between men and women. This is consistent with the changes observed for serum sodium, thirst, SBP, and plasma AVP, all of which increased to a similar extent between the sexes. However, functional connectivity between the SFO and OVLT increased in men but decreased in women, indicating a sex-specific response. Interestingly, serum testosterone was positively correlated with the change in SFO-OVLT functional connectivity in men and women combined, suggesting that testosterone may impact this response. Collectively, these results demonstrate that, in response to acute relative hypernatremia, these salt sensing and sympathoregulatory brain regions are activated similarly in both men and women tested during the follicular menstrual cycle phase (as assessed by fALFF); however, men seem to have a more synchronized neural response between the SFO and OVLT (as assessed via functional connectivity). This suggests that these regions are more tightly coupled in their neural response to acute hypernatremia in men. These findings set the stage for additional studies to investigate mechanisms of central salt sensing in humans, central salt sensing in the context of chronic salt loading, and sex differences across the lifespan.