Brain sodium sensing for regulation of thirst, salt appetite, and blood pressure

Abstract

The brain possesses intricate mechanisms for monitoring sodium (Na) levels in body fluids. During prolonged dehydration, the brain detects variations in body fluids and produces sensations of thirst and aversions to salty tastes. At the core of these processes Na_x , the brain's Na sensor, exists. Specialized neural nuclei, namely the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which lack the blood-brain barrier, play pivotal roles. Within the glia enveloping the neurons in these regions, Na_x collaborates with Na⁺ /K⁺ -ATPase and glycolytic enzymes to drive glycolysis in response to elevated Na levels. Lactate released from these glia cells activates nearby inhibitory neurons. The SFO hosts distinct types of angiotensin II-sensitive neurons encoding thirst and salt appetite, respectively. During dehydration, Na_x -activated inhibitory neurons suppress salt-appetite neuron's activity, whereas salt deficiency reduces thirst neuron's activity through cholecystokinin. Prolonged dehydration increases the Na sensitivity of Na_x via increased endothelin expression in the SFO. So far, patients with essential hypernatremia have been reported to lose thirst and antidiuretic hormone release due to Na_x -targeting autoantibodies. Inflammation in the SFO underlies the symptoms. Furthermore, Na_x activation in the OVLT, driven by Na retention, stimulates the sympathetic nervous system via acid-sensing ion channels, contributing to a blood pressure elevation.

Keywords: Nax; OVLT; blood pressure; salt appetite; subfornical organ; thirst.

FIGURE 1

Na_x channel and its expression loci in the brain. (a) Phylogenetic tree of voltage‐gated Na channel α subunits. (b) Location of sensory circumventricular organs (red) in a sagittal view of human brains. Reproduced with minor modifications from Goldin et al. (2000) for (a).

FIGURE 2

Relationship between current density (current amplitude/cell capacitance) and [Na⁺]_o in the presence or absence of ET‐3 (1 nM). Blue area shows the normal range of blood [Na⁺]. This variability is due to individual differences, and the sodium levels of each individual are strictly maintained.

FIGURE 3

[Na⁺]‐sensing mechanism and Na_x‐dependent control of lactate production in the glia (ependymal cells and astrocytes) in the subfornical organ (SFO)/organum vasculosum of the lamina terminalis (OVLT). When [Na⁺]_o surpasses a threshold, Na_x channels open, triggering Na⁺/K⁺‐ATPase activation and accelerating ATP consumption. To meet ATP demands, anaerobic glycolysis is boosted in glia, enhancing glucose uptake. The glia release lactate, the glycolysis end product. ET‐3, endothelin‐3; ET_BR, endothelin receptor type B. Modified from Shimizu et al. (2007).

FIGURE 4

Lactate signaling by glia to control neighboring inhibitory neurons. (a) Schematic outlining explaining lactate transport from glia to neurons. (b) Depolarization mechanism following the lactate transport. MCT, monocarboxylate transporter.

FIGURE 5

Na/water balance in body fluids and physiological responses. Blood angiotensin II levels increase under any of the three conditions. The physiological responses in each square contribute to homeostatic recovery from each condition.

FIGURE 6

Regulation of thirst and salt appetite from the subfornical organ (SFO). The SFO contains neuronal cell bodies and fenestrated capillaries allowing angiotensin II (Ang II) entry. Under dehydrated conditions (top, left), Ang II stimulates both SFO(→ventral bed nucleus of the stria terminalis, vBNST) neurons (for salt appetite) and SFO(→organum vasculosum of the lamina terminalis, OVLT) neurons (for thirst). However, Na_x channels in glia respond to increased [Na⁺]_o, activating lactate signaling, leading to activation of GABAergic neurons and suppression of SFO(→vBNST) neurons. In Na‐depleted conditions (top, right), although Ang II stimulates both types, cholecystokinin (CCK) neurons in the SFO are activated and suppress the activities of SFO(→OVLT) neurons via GABAergic activation, inhibiting water intake. Ang II successfully activates only SFO(→vBNST) neurons, enhancing salt appetite. Salt depletion triggers aldosterone release, which affects the gene expression profiles in the nucleus of the solitary tract (NTS) neurons. Consequently, enhancement of the neuronal activity occurs, and salt appetite is induced. Under both water and Na depletion (bottom), Ang II activates both types of neurons in the absence of Na_x or CCK signals. Modified from Matsuda et al. (2017).

FIGURE 7

Na⁺ sensing in the organum vasculosum of the lamina terminalis (OVLT) and regulation of thirst and blood pressure. Increased [Na⁺]_o activates Slc9a4‐positive neurons directly to induce thirst. Na_x channels in glias (ependymal cells and astrocytes) are also activated in responding to [Na⁺]_o. This activation leads to 5,6‐ epoxyeicosatrienoic acid (EET) synthesis. Released EETs activate TRPV4 channels of neighboring neurons, which potentially controls water intake behavior. Na_x activation also induces H⁺ (with lactic acid ions) release from Na_x‐expressing ependymal cells and astrocytes through monocarboxylate transporters (MCTs). The resultant extracellular acidification stimulates OVLT(→paraventricular nucleus, PVN) neurons via ASIC1a activation. Activation of PVN, the central hub of sympathetic control, induces elevation in blood pressure through the activation of sympathetic nerves (SN). Modified from Sakuta et al. (2016) and Nomura et al. (2019).