Summary: Researchers have identified a population of neurons that detect sodium deficiency and drive the behavioral urge to seek and consume salt.
Source: BIDMC.
Salt is essential for life. Although a high-salt diet has been linked to hypertension and cardiovascular disease in many Americans, sodium remains a critical mineral that the body needs to maintain fluid balance, support cellular function, and regulate blood pressure. As sodium is lost through normal excretion and metabolic processes, the body responds by releasing hormones that signal a need to restore sodium levels. Until now, the precise neural circuitry that translates these hormonal signals into a targeted appetite for salt was poorly understood.
Researchers in the Division of Endocrinology, Diabetes and Metabolism at Beth Israel Deaconess Medical Center (BIDMC) have mapped a key part of that circuitry. In a paper published in the journal Neuron, the team led by Bradford Lowell, MD, PhD, identified a specific subpopulation of neurons that respond to sodium deficiency and outlined how these neurons interact with hormonal signals to generate salt-seeking behavior.
“We identified a distinct circuit in the brain that detects sodium deficiency and triggers an appetite specifically for sodium to correct the deficit,” said Jon M. Resch, PhD, a postdoctoral fellow in Lowell’s lab and co-first author on the study. “This work shows that sodium ingestion is tightly regulated by the brain, and that dysfunction within these neurons could contribute to either excessive or insufficient sodium intake, with potential long-term effects on cardiovascular health.”
The investigators concentrated on a subgroup of neurons first described about a decade ago by co-corresponding author Joel Geerling, MD, PhD. These neurons, referred to as NTSHSD2, are located in the nucleus of the solitary tract (NTS), a brain region that integrates visceral signals. Using mouse models made sodium-deficient, the team demonstrated that NTSHSD2 neurons become activated when the body lacks sodium. They further showed that aldosterone—the hormone released during sodium shortage—enhances these neurons’ responsiveness.
Resch noted an intriguing characteristic of the NTSHSD2 neurons: they appear to be strongly influenced by circulating hormones such as aldosterone and are less dependent on synaptic input from other neurons. “This reliance on hormonal cues rather than upstream neural input is a distinctive and unexpected feature of these cells,” he said, though he acknowledged that more research is needed to fully understand the inputs and regulation.
Importantly, the researchers found that NTSHSD2 neurons are necessary but not sufficient on their own to trigger salt consumption in animals that are not sodium-deficient. When these neurons were artificially activated in sodium-replete mice, increased salt intake occurred only if angiotensin II (ATII)—another hormone released during sodium deficiency—was simultaneously present. This result indicates that a second, ATII-sensitive population of neurons works in concert with NTSHSD2 neurons to produce the rapid and robust sodium appetite observed during deficiency.
The study shows that the sodium appetite arises from the combined action of two distinct, hormone-responsive neuronal groups—those sensitive to aldosterone and those influenced by angiotensin II. Only when both pathways are engaged does the characteristic, rapid onset of salt-seeking behavior occur, as seen in experimentally sodium-deficient mice. This dual-pathway model provides a physiological framework that supports ideas about sodium appetite originally proposed in the early 1980s, giving modern experimental evidence for how the brain integrates hormonal signals to control a targeted mineral appetite.
“Key questions remain, such as the precise brain targets where ATII acts and the detailed mechanisms by which ATII-sensitive neurons coordinate with NTSHSD2 neurons,” Resch said. “Our group has already begun follow-up studies aimed at identifying the ATII-responsive neuronal population and mapping the synaptic and molecular links that produce the sodium appetite.”
The study’s authors include Jon M. Resch, PhD; Henning Fenselau, PhD; Joseph C. Madera, PhD; Chen Wu, PhD; John N. Campbell, PhD; Anna Lyubetskaya, PhD; Brian A. Dawes, PhD; Linus T. Tsai, MD, PhD; Monica M. Li, PhD; Yoav Livneh, PhD; Qingen Ke, MD; Peter M. Kang, MD; Geza Fejes-Toth, MD, PhD; and Aniko Naray-Fejes-Toth, MD. The work was conducted at Beth Israel Deaconess Medical Center, with contributions from the Geisel School of Medicine at Dartmouth.
Funding: This research was supported by National Institutes of Health grants R01 DK075632, R01 DK096010, R01 DK089044, R01 DK111401, P30 DK046200, P30 DK057521, K08 NS099425, and F32 DK103387; an American Heart Association postdoctoral fellowship (14POST20100011); and an EMBO postdoctoral fellowship.
Source: Jacqueline Mitchell, BIDMC. Original Research: Manuscript published in Neuron.
BIDMC. “Pass the Salt: Mapping the Neurons That Drive Salt Cravings.” NeuroscienceNews, 27 September 2017.