Neural Circuits Underlying Salt-Taste Valence

Citation

Zhang, Yameng (2026) Neural Circuits Underlying Salt-Taste Valence. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/kp37-4v28. https://resolver.caltech.edu/CaltechTHESIS:12102025-235050354

Abstract

Salt consumption is unique among the five basic tastes. The perception of salty taste revealed a concentration-dependent and internal-state-dependent valence pattern. Low concentrations of salt trigger sodium-specific taste receptors while high concentrations recruit bitter and sour pathways, which have been investigated by previous research and proven with daily experience. I focus on the dynamic nature of salt perception, in the perspective of physiological states.

In calorie restricted state, food cues become more appetitive, but in sodium depletion state, the hedonic value of salt fundamentally reversed. High concentrations of salt induce innate aversion under sated states, whereas such aversive stimuli transform into appetitive ones under sodium depletion. Neural mechanisms underlying this state-dependent salt valence switch are poorly understood. Using transcriptomics state-to-cell-type mapping and neural manipulations, we show that positive and negative valences of salt are controlled by anatomically distinct neural circuits in the mammalian brain. The hindbrain interoceptive circuit regulates sodium-specific appetitive drive, whereas behavioral tolerance of aversive salts is encoded by a dedicated class of neurons in the forebrain lamina terminalis (LT) expressing prostaglandin E2 (PGE2) receptor, Ptger3. We show that these LT neurons regulate salt tolerance by selectively modulating aversive taste sensitivity, partly through a PGE2-Ptger3 axis. These results reveal the bimodal regulation of appetitive and tolerance signals toward salt, which together dictate the amount of sodium consumption under different internal states.

Maintaining the fluid balance requires complex crosstalk within the neural circuits and endocrine systems through the brain-body axis. Despite the prevalence of fluid balance dysregulation and salt overconsumption in modern life, its health relevance remains underappreciated. I have been attracted to the global salt overconsumption crisis from the start of my Ph. D. study. The current approaches to regulate salt intake rely heavily on imperfect salt substitutes. The PGE2-Ptger3 brain-body axis posed a new top-down approach to reduce salt intake. Interestingly, PGE2 is a critical biomarker in pro-inflammation state. It has been investigated that high salt intake induces chronic inflammation, desensitization of salty tastes, and intensified craving for consumption. I regard my research of the tolerance circuit as an entry point and hope future research into inflammation and its role in salt intake can be translated into concrete salt reduction solutions.