Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling

Sodium deficiency increases angiotensin II (ATII) and aldosterone, which synergistically stimulate sodium retention and consumption. Recently, ATII-responsive neurons in the subfornical organ (SFO) and aldosterone-sensitive neurons in the nucleus of the solitary tract (NTSHSD2 neurons) were shown to drive sodium appetite. Here we investigate the basis for NTSHSD2 neuron activation, identify the circuit by which NTSHSD2 neurons drive appetite, and uncover an interaction between the NTSHSD2 circuit and ATII signaling. NTSHSD2 neurons respond to sodium deficiency with spontaneous pacemaker-like activity—the consequence of “cardiac” HCN and Nav1.5 channels. Remarkably, NTSHSD2 neurons are necessary for sodium appetite, and with concurrent ATII signaling their activity is sufficient to produce rapid consumption. Importantly, NTSHSD2 neurons stimulate appetite via projections to the vlBNST, which is also the effector site for ATII-responsive SFO neurons. The interaction between angiotensin signaling and NTSHSD2 neurons provides a neuronal context for the long-standing “synergy hypothesis” of sodium appetite regulation. •Sodium deficiency generates pacemaker-like firing of NTSHSD2 neurons•HCN, Nav1.5, and Cav2.3 channels drive state-dependent activity of NTSHSD2 neurons•Sodium appetite is produced via synergy between NTSHSD2 neurons and angiotensin II•NTSHSD2 neurons promote sodium ingestion through projections to the vlBNST Resch et al. demonstrate pacemaker-like firing of aldosterone-sensing NTSHSD2 neurons during sodium deficiency and a synergistic relationship between NTSHSD2 neurons and angiotensin II signaling that drives rapid sodium appetite. NTSHSD2 neurons induce sodium ingestion through projections to the vlBNST.