Central Regulation of Sodium Appetite via Synergistic Action of RAAS-sensitive Neurons

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PROJECT SUMMARY The motivation to consume sodium, often referred to as "sodium (or salt) appetite", is a hard-wired neural response to sodium deficiency regulated by the Renin-Angiotensin-Aldosterone System (RAAS). Impaired function of this system results in inappropriate sodium ingestion that can have deleterious effects on cardiovascular health. The studies and career development activities in this K99/R00 proposal are designed to provide the candidate, Dr. Jon Resch, with the training necessary to become an independent investigator with a research program examining the neural control of sodium appetite. Recently two RAAS-sensitive neuronal populations have been shown to regulate sodium appetite: aldosterone-sensing neurons in the nucleus of the solitary tract (NTSHsd11b2 neurons) and a subpopulation of angiotensin II (AngII)-sensing neurons in the subfornical organ (SFO). Importantly, both NTSHsd11b2 neurons and AngII-sensing SFO neurons are necessary for deficiency-induced sodium appetite, and NTSHsd11b2 neurons require concurrent AngII signaling to drive rapid and robust sodium consumption. Furthermore, both RAAS-sensitive populations promote sodium ingestion via projections to the ventral lateral bed nucleus of the stria terminalis (vlBNST). This strongly suggests that the vlBNST is the critical site where neural processing occurs to coordinate sodium appetite. However, the functional complexity and neurochemical heterogeneity of the vlBNST poses a significant challenge to finding and investigating the neurons within it that regulate sodium appetite. In order to elucidate the neural circuits that control sodium appetite, the proposed research will (1) confirm the site of AngII signaling that enables NTSHsd11b2 neurons to drive sodium appetite, (2) decipher the wiring diagram of RAAS- sensitive inputs to the vlBNST, (3) use high-throughput single-cell transcriptomics to generate a "molecular census" of vlBNST neurons, and (4) identify the molecular signature of vlBNST "sodium appetite" neurons. The results of these experiments will form the foundation for many future studies regarding sodium appetite control by the BNST and the downstream circuits through which these neurons produce the motivation to consume sodium. The proposed research and training will be conducted within the Endocrine Division of the Department of Medicine at Beth Israel Deaconess Medical Center, and will ensure the Dr. Resch's successful transition to scientific independence. Dr. Resch will receive training in CRISPR/Cas9-based methods for mouse genetic engineering from his primary mentor, Dr. Bradford Lowell, and in single-cell transcriptomics from his advisory committee members, Drs. Evan Rosen and Linus Tsai. Furthermore, through acquiring the aforementioned technical expertise, coursework, attendance of scientific meetings, and lab management training from his primary mentor during the initial K99 award period, Dr. Resch will cultivate an independent research program studying the neural control of sodium appetite.