Brain Structure and Function

, Volume 224, Issue 1, pp 387–417 | Cite as

Aldosterone-sensitive HSD2 neurons in mice

  • Silvia Gasparini
  • Jon M. Resch
  • Sowmya V. Narayan
  • Lila Peltekian
  • Gabrielle N. Iverson
  • Samyukta Karthik
  • Joel C. GeerlingEmail author
Original Article


Sodium deficiency elevates aldosterone, which in addition to epithelial tissues acts on the brain to promote dysphoric symptoms and salt intake. Aldosterone boosts the activity of neurons that express 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2), a hallmark of aldosterone-sensitive cells. To better characterize these neurons, we combine immunolabeling and in situ hybridization with fate mapping and Cre-conditional axon tracing in mice. Many cells throughout the brain have a developmental history of Hsd11b2 expression, but in the adult brain one small brainstem region with a leaky blood–brain barrier contains HSD2 neurons. These neurons express Hsd11b2, Nr3c2 (mineralocorticoid receptor), Agtr1a (angiotensin receptor), Slc17a6 (vesicular glutamate transporter 2), Phox2b, and Nxph4; many also express Cartpt or Lmx1b. No HSD2 neurons express cholinergic, monoaminergic, or several other neuropeptidergic markers. Their axons project to the parabrachial complex (PB), where they intermingle with AgRP-immunoreactive axons to form dense terminal fields overlapping FoxP2 neurons in the central lateral subnucleus (PBcL) and pre-locus coeruleus (pLC). Their axons also extend to the forebrain, intermingling with AgRP- and CGRP-immunoreactive axons to form dense terminals surrounding GABAergic neurons in the ventrolateral bed nucleus of the stria terminalis (BSTvL). Sparse axons target the periaqueductal gray, ventral tegmental area, lateral hypothalamic area, paraventricular hypothalamic nucleus, and central nucleus of the amygdala. Dual retrograde tracing revealed that largely separate HSD2 neurons project to pLC/PB or BSTvL. This projection pattern raises the possibility that a subset of HSD2 neurons promotes the dysphoric, anorexic, and anhedonic symptoms of hyperaldosteronism via AgRP-inhibited relay neurons in PB.


Sodium appetite Salt appetite 11-Beta-hydroxysteroid dehydrogenase type 2 Mineralocorticoid receptor Aldosterone Nucleus of the solitary tract Angiotensin II Dietary sodium Dietary sodium deficiency Dietary sodium deprivation 



We thank Richard Palmiter and Aniko Fejes-Toth for sharing Hsd11b2 Cre-driver mice; David Olson for L10GFP Cre-reporter mice; and Justin Grobe, Huxing Cui, and Kenji Saito for Agtr1a-GFP mice and brainstem tissue. Hideki Enomoto of Kobe University generously provided an aliquot of GP-anti-Phox2b, and Carmen Birchmeier generously provided an aliquot of GP-anti-Lmx1b antiserum. Finally, we thank Brad Lowell for mentorship and for material support for much of this work.


Grant sponsors: NIH F32 DK103387 (JMR). NIH K08 NS099425 (JCG). Aging Mind and Brain Initiative, University of Iowa Center for Aging (JCG).

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

429_2018_1778_MOESM1_ESM.pdf (619 kb)
Supplemental figure A1: Whole-slide imaging of a representative brain after immunohistochemical staining for HSD2 using nickel-DAB for maximum sensitivity (1-in-3, 40 µm tissue sections through a full mouse brain). No brain regions contain HSD2 immunoreactivity visible at low magnification (PDF 619 KB)
429_2018_1778_MOESM2_ESM.pdf (1.3 mb)
Supplemental figure A2: High magnification images of every brain region previously reported to express Hsd11b2 mRNA or contain immunoreactivity for HSD2 (page 2). The NTS contains intense HSD2 immunoreactivity, but no other region contains labeling above background levels. Scale bars are 200 µm and apply to all panels (PDF 1302 KB)
429_2018_1778_MOESM3_ESM.pdf (10.3 mb)
Supplemental figure A3: Whole-slide imaging of a representative brain with tdTomato nuclear reporter for Hsd11b2 (Hsd11b2Cre;Ai75-lsl-Tomato, 1-in-3 series of 40 µm sections). This Ai75 Cre-reporter is expressed in sparse, small cells in every brain region, at every level, and in neurons in a variety of regions outside the NTS, including the cerebellar granule cell layer and some of its connections (pontine nuclei, lateral reticular nucleus, external cuneate nucleus), superior colliculus, and several parts of the diencephalon (PDF 10583 KB)
429_2018_1778_MOESM4_ESM.pdf (3.2 mb)
Supplemental figure A3: Whole-slide imaging of a representative brain with tdTomato nuclear reporter for Hsd11b2 (Hsd11b2Cre;Ai75-lsl-Tomato, 1-in-3 series of 40 µm sections). This Ai75 Cre-reporter is expressed in sparse, small cells in every brain region, at every level, and in neurons in a variety of regions outside the NTS, including the cerebellar granule cell layer and some of its connections (pontine nuclei, lateral reticular nucleus, external cuneate nucleus), superior colliculus, and several parts of the diencephalon (PDF 3241 KB)
429_2018_1778_MOESM5_ESM.pdf (27.8 mb)
Supplemental figure A4: Examples of Syp-mCherry labeling in HSD2 axons and boutons in brain tissue sections from an Hsd11b2-Cre mouse injected with AAV-DIO-Syp-mCherry into the NTS (injection site in Figure 6). We immunolabeled mCherry using nickel-DAB (black) and added a light Nissl counterstain (blue-gray) for cytoarchitectural reference. For each image, an inset (adapted from Figure 7) shows the level and location (red box). (A) Lightly labeled axons pass through the intermediate reticular formation of the caudal medulla; (B) dense axon-terminal field in the pre-locus coeruleus (pLC); (C) less-dense axons and boutons in the rostral pLC and medial parabrachial nucleus (PB); (D) dense axon-terminal field in the central lateral PB (PBcL), bordering the superior cerebellar peduncle; (E) lightly labeled axons course dorsally around the sensory and motor trigeminal nuclei before turning caudally to reach the PB; (F) light axonal branching and bouton labeling in the lateral hypothalamic area (LHA)/parasubthalamic nucleus (PSTN); (G) small cluster of boutons formed by a single branching axon in the central nucleus of the amygdala (CeA); (H) few, sparse axon branches and boutons in the ventral midbrain; (I-J) caudal and middle levels of the dense, focal axon-terminal field in the ventrolateral bed nucleus of the stria terminalis (BSTvL). Scale bars are 50 µm (PDF 28465 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of IowaIowa CityUSA
  2. 2.Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA

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