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

Abstract

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 (NTS^HSD2 neurons) were shown to drive sodium appetite. Here we investigate the basis for NTS^HSD2 neuron activation, identify the circuit by which NTS^HSD2 neurons drive appetite, and uncover an interaction between the NTS^HSD2 circuit and ATII signaling. NTS^HSD2 neurons respond to sodium deficiency with spontaneous pacemaker-like activity-the consequence of "cardiac" HCN and Na_v1.5 channels. Remarkably, NTS^HSD2 neurons are necessary for sodium appetite, and with concurrent ATII signaling their activity is sufficient to produce rapid consumption. Importantly, NTS^HSD2 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 NTS^HSD2 neurons provides a neuronal context for the long-standing "synergy hypothesis" of sodium appetite regulation.

Keywords: 11β-Hydroxysteroid dehydrogenase 2; HCN channels; Na(v)1.5; aldosterone; angiotensin II; bed nucleus of the stria terminalis; electrophysiology; nucleus of the solitary tract; pacemaker activity; sodium appetite.