Sex Differences in Central Neural Activation During Acute Hypernatremia

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PROJECT SUMMARY/ABSTRACT Blood pressure (BP)-related diseases continue to be a major public health challenge in both sexes. Men have a higher prevalence of hypertension compared to women until about age 60, after which prevalence is greater in women, reflecting the cardioprotective role of female sex hormones. The high incidence of hypertension in adults is associated with high dietary sodium intake. Thus, investigating sex differences in responses to sodium may be important in understanding these health disparities between men and women. Central sodium sensing is critical in mediating neurohormonal responses to the relative hypernatremia associated with high salt intake. The circumventricular organs (CVOs), including the organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO), lack a complete blood brain barrier and contain osmosensitive neurons capable of sensing changes in sodium concentration in the blood. The CVOs also mediate sodium-induced changes in sympathetic nerve activity (SNA), vasopressin (AVP), thirst, and BP. Studies in humans show increased activation of the CVOs during acute hypernatremia (hypertonic saline infusion), which is similar to the underappreciated relative hypernatremia that occurs with high sodium intake. However, no human studies have investigated whether there are sex differences in central neural activation during acute hypernatremia. Therefore, the focus of this proposal is to investigate sex differences in functional connectivity of sodium sensing brain regions (SFO, OVLT) and brain regions involved in sympathetic outflow (rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM)) during acute hypernatremia (via hypertonic saline infusion) using blood oxygen level dependent (BOLD) fMRI. We will also assess whether these responses are associated with changes in AVP, norepinephrine (NE), thirst, and BP. This proposal involves 2 specific aims: aim 1 will assess sex differences in change in functional connectivity between sodium sensing brain regions (SFO, OVLT); aim 2 will assess sex differences in change in functional connectivity between sympathoregulatory brain regions (RVLM, NTS, CVLM). We hypothesize that acute hypernatremia will increase functional connectivity between sodium sensing brain regions (Aim 1) and increase connectivity with the RVLM and decrease connectivity with the NTS and CVLM (Aim 2). We hypothesize that men will have greater responses since (1) in salt sensitive rodent models, male animals display larger changes in arterial BP; (2) men have greater AVP release in response to hypertonic saline infusion; and (3) men have greater MSNA, BP, and forebrain BOLD fMRI responses to various cardiovascular stressors. This proposal has the potential to offer important insight into sex-specific mechanisms of BP regulation and fluid balance and will provide the trainee with specific instruction in BOLD fMRI and technical writing, which are critical in his development into a productive research scientist.