A neural basis for the tonic suppression of sodium appetite

1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea. 2The Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA. *e-mail: chen.liu@utsouthwestern.edu; jwsohn@kaist.ac.kr Sodium ion (Na+) is an essential mineral to maintain extracellular fluid (ECF) and blood volume. Depletion of sodium leads to an increase in sodium appetite—a strong motivation for animals to consume otherwise aversive concentrations of sodium1. Recently, several studies identified neural circuits and molecular mechanisms underlying the promotion of sodium appetite2–4. However, sodium appetite is not strongly manifested in normal conditions, suggesting that it might be suppressed. Indeed, high concentrations of sodium are typically aversive in the euvolemic state, which is in part mediated by a peripheral mechanism5. However, a central mechanism underlying the suppression of sodium appetite is currently unknown. Previous pharmacological studies suggested that the LPBN plays a role in suppressing sodium appetite6,7. However, lesions to the LPBN failed to increase sodium appetite8,9, which otherwise seems to suggest that the LPBN is not involved in suppressing sodium appetite during euvolemic states. This discrepancy might be due in part to the heterogeneous nature of the LPBN, as this nucleus has been shown to also contain a population of neurons that putatively promote sodium appetite10. Thus, the identity of LPBN neuronal subpopulations that suppress sodium appetite remains to be revealed. Brain serotonin receptors were proposed to control sodium appetite, but the results were not consistent between studies, possibly owing to the use of different drugs11,12. Likewise, infusions of drugs that affect serotonergic signaling within the LPBN have been shown to have mixed effects on sodium intake13,14. These pharmacological studies suggest that serotonergic mechanisms within the LPBN contribute to alter sodium appetite. However, they lack cellular and temporal specificity, which limits the interpretation of these results. Notably, no information is currently available regarding the physiological role of specific types of serotonin receptors expressed by LPBN neurons in regulating sodium balance. To resolve the issues raised by past studies, we genetically segregated a population of LPBN neurons that express Htr2c and investigated their potential role and the relevant circuitry in mediating the suppression of sodium appetite. Furthermore, we explored the physiological role of this neuronal population in the control of sodium appetite.