Aldosterone target neurons in the nucleus tractus solitarius drive sodium appetite

Abstract

Sodium appetite can be enhanced by the adrenal steroid aldosterone via an unknown brain mechanism. A novel group of neurons in the nucleus tractus solitarius expresses the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, which makes them selectively responsive to aldosterone. Their activation parallels sodium appetite in different paradigms of salt loss even in the absence of aldosterone. These unique aldosterone target neurons may represent a previously unrecognized central convergence point at which hormonal and neural signals can be integrated to drive sodium appetite.

Figure 1.

The location of neurons immunoreactive for the enzyme HSD2, which is critical for aldosterone selectivity, is shown at three rostrocaudal levels of the dorsomedial medulla (A–C). These neurons (green) lie within the NTS from just rostral to area postrema (A) through ∼1 mm caudal (C). Rostrocaudal distances (top right; in micrometers) are relative to the level of calamus scriptorius (C). D, MR immunoreactivity (red) within the nuclei and perinuclear cytoplasm of HSD2-immunoreactive neurons (green) in the NTS from an animal with high plasma aldosterone. AP, Area postrema; 4V, fourth ventricle; med, medial subnucleus of NTS; com, commissural subnucleus of NTS; SubPD, dorsal subpostremal zone; T, solitary tract; X, dorsal motor nucleus of the vagus; XII, hypoglossal nucleus.

Figure 2.

HSD2 neurons are aldosterone-sensitive and aldosterone-selective. The percentage of HSD2-immunoreactive neurons (green) in the NTS containing dense nuclear MR immunoreactivity (red) is shown from adrenalectomized rats that were administered vehicle (veh), aldosterone (aldo), corticosterone (cort), or corticosterone plus aldosterone (cort + aldo). This percentage represents steroid binding and MR translocation from the cytoplasm into the nucleus. Error bars represent SEM.

Figure 3.

Sodium deprivation increases c-Fos activation in HSD2 neurons in the NTS. A, Many HSD2 neurons (green) contain c-Fos-immunoreactive nuclei (red) after dietary sodium deprivation (7 d). B, In 6 d sodium-deprived rats, 1 d of sodium repletion eliminates c-Fos expression in HSD2 neurons. C, The percentage of c-Fos-positive HSD2 neurons increases with time in sodium-deprived intact rats (filled blue circles), but 1 d of high-sodium diet consistently abolishes this activation (open black circles). D, The elevation in c-Fos-positive HSD2 neurons (32.5 ± 4.5%) caused by 8 d of dietary sodium deprivation is nearly abolished within 2 h of access to 3% saline. Error bars represent SEM.

Figure 4.

When adrenalectomized animals (filled circles) are sodium-deprived, HSD2 neurons show elevated c-Fos activation by just 1 d after sodium is removed. This elevated activation peaks at day 3 and then parallels the pattern of adrenal-intact (sham-operated) rats. In sham-adrenalectomized (sham-adx) control rats subjected to the same dietary sodium deprivation protocol (open circles), HSD2 neuron activation was delayed, similar to intact rats. Error bars represent SEM.