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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

Abstract

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.

Keywords

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 

Notes

Acknowledgements

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.

Funding

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)

References

  1. Aponte Y, Atasoy D, Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14(3):351–355Google Scholar
  2. Arriza JL, Simerly RB, Swanson LW, Evans RM (1988) The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1(9):887–900Google Scholar
  3. Askew ML, Muckelrath HD, Johnston JR, Curtis KS (2015) Neuroanatomical association of hypothalamic HSD2-containing neurons with ERalpha, catecholamines, or oxytocin: implications for feeding? Front Syst Neurosci 9:91Google Scholar
  4. Aston-Jones G, Delfs JM, Druhan J, Zhu Y (1999) The bed nucleus of the stria terminalis. A target site for noradrenergic actions in opiate withdrawal. Ann N Y Acad Sci 877:486–498Google Scholar
  5. Bard P (1928) A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system. Am J Physiol 84(3):490–515Google Scholar
  6. Betley JN, Cao ZF, Ritola KD, Sternson SM (2013) Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155(6):1337–1350Google Scholar
  7. Broadwell RD, Sofroniew MV (1993) Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system. Exp Neurol 120(2):245–263Google Scholar
  8. Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD (2015) Vagal sensory neuron subtypes that differentially control breathing. Cell 161(3):622–633Google Scholar
  9. Chang SE, Smedley EB, Stansfield KJ, Stott JJ, Smith KS (2017) optogenetic inhibition of ventral pallidum neurons impairs context-driven salt seeking. J Neurosci 37(23):5670–5680Google Scholar
  10. Chen S, Aston-Jones G (1995) Evidence that cholera toxin B subunit (CTb) can be avidly taken up and transported by fibers of passage. Brain Res 674(1):107–111Google Scholar
  11. Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 3(8):655–666Google Scholar
  12. Dai JX, Hu ZL, Shi M, Guo C, Ding YQ (2008) Postnatal ontogeny of the transcription factor Lmx1b in the mouse central nervous system. J Comp Neurol 509(4):341–355Google Scholar
  13. de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MH, Hasselmann H, Kliegel D, Joels M (2016) Stress and depression: a crucial role of the mineralocorticoid receptor. J Neuroendocrinol 28(8)Google Scholar
  14. Denton DA, Sabine JR (1961) The selective appetite for Na ions shown by Na ion-deficient sheep. J Physiol 157:97–116Google Scholar
  15. Diaz R, Brown RW, Seckl JR (1998) Distinct ontogeny of glucocorticoid and mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase types I and II mRNAs in the fetal rat brain suggest a complex control of glucocorticoid actions. J Neurosci 18(7):2570–2580Google Scholar
  16. Dong HW (2008) Allen reference atlas: a digital color brain atlas of the C57Black/6J male mouse. Wiley. ix, Hoboken, 366 p. pGoogle Scholar
  17. Dong HW, Petrovich GD, Watts AG, Swanson LW (2001) Basic organization of projections from the oval and fusiform nuclei of the bed nuclei of the stria terminalis in adult rat brain. J Comp Neurol 436(4):430–455Google Scholar
  18. Egli RE, Kash TL, Choo K, Savchenko V, Matthews RT, Blakely RD, Winder DG (2005) Norepinephrine modulates glutamatergic transmission in the bed nucleus of the stria terminalis. Neuropsychopharmacology 30(4):657–668Google Scholar
  19. Epstein AN (1982) Mineralocorticoids and cerebral angiotensin may act together to produce sodium appetite. Peptides 3(3):493–494Google Scholar
  20. Essner RA, Smith AG, Jamnik AA, Ryba AR, Trutner ZD, Carter ME (2017) AgRP neurons can increase food intake during conditions of appetite suppression and inhibit anorexigenic parabrachial neurons. J Neurosci 37(36):8678–8687Google Scholar
  21. Evans LC, Ivy JR, Wyrwoll C, McNairn JA, Menzies RI, Christensen TH, Al-Dujaili EA, Kenyon CJ, Mullins JJ, Seckl JR, Holmes MC, Bailey MA (2016) Conditional deletion of Hsd11b2 in the brain causes salt appetite and hypertension. Circulation 133(14):1360–1370Google Scholar
  22. Fitts DA (1991) Effects of lesions of the ventral ventral median preoptic nucleus or subfornical organ on drinking and salt appetite after deoxycorticosterone acetate or yohimbine. Behav Neurosci 105(5):721–726Google Scholar
  23. Fluharty SJ, Epstein AN (1983) Sodium appetite elicited by intracerebroventricular infusion of angiotensin II in the rat: II. Synergistic interaction with systemic mineralocorticoids. Behav Neurosci 97(5):746–758Google Scholar
  24. Formenti S, Bassi M, Nakamura NB, Schoorlemmer GH, Menani JV, Colombari E (2013) Hindbrain mineralocorticoid mechanisms on sodium appetite. Am J Physiol Regul Integr Comp Physiol 304(3):R252–R259Google Scholar
  25. Franklin KBJ, Paxinos G (2013) Paxinos and Franklin’s The mouse brain in stereotaxic coordinates. Academic Press, AmsterdamGoogle Scholar
  26. Funder J, Myles K (1996) Exclusion of corticosterone from epithelial mineralocorticoid receptors is insufficient for selectivity of aldosterone action: in vivo binding studies. Endocrinology 137(12):5264–5268Google Scholar
  27. Funder JW, Pearce PT, Smith R, Smith AI (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242(4878):583–585Google Scholar
  28. Garfield AS, Li C, Madara JC, Shah BP, Webber E, Steger JS, Campbell JN, Gavrilova O, Lee CE, Olson DP, Elmquist JK, Tannous BA, Krashes MJ, Lowell BB (2015) A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18(6):863–871Google Scholar
  29. Geerling JC, Loewy AD (2006a) Aldosterone-sensitive neurons in the nucleus of the solitary tract: bidirectional connections with the central nucleus of the amygdala. J Comp Neurol 497(4):646–657Google Scholar
  30. Geerling JC, Loewy AD (2006b) Aldosterone-sensitive neurons in the nucleus of the solitary tract: efferent projections. J Comp Neurol 497(2):223–250Google Scholar
  31. Geerling JC, Loewy AD (2006c) Aldosterone-sensitive NTS neurons are inhibited by saline ingestion during chronic mineralocorticoid treatment. Brain Res 1115(1):54–64Google Scholar
  32. Geerling JC, Loewy AD (2007a) 11beta-hydroxysteroid dehydrogenase 2 vs. transgene: discrepant loci of expression in the adult brain. Am J Physiol Renal Physiol 293(1):F440–F441 (author reply F442–F443) Google Scholar
  33. Geerling JC, Loewy AD (2007b) Sodium depletion activates the aldosterone-sensitive neurons in the NTS independently of thirst. Am J Physiol Regul Integr Comp Physiol 292(3):R1338–R1348Google Scholar
  34. Geerling JC, Loewy AD (2007c) Sodium deprivation and salt intake activate separate neuronal subpopulations in the nucleus of the solitary tract and the parabrachial complex. J Comp Neurol 504(4):379–403Google Scholar
  35. Geerling JC, Loewy AD (2008) Central regulation of sodium appetite. Exp Physiol 93(2):177–209Google Scholar
  36. Geerling JC, Loewy AD (2009) Aldosterone in the brain. Am J Physiol Renal Physiol 297(3):F559–F576Google Scholar
  37. Geerling JC, Engeland WC, Kawata M, Loewy AD (2006a) Aldosterone target neurons in the nucleus tractus solitarius drive sodium appetite. J Neurosci 26(2):411–417Google Scholar
  38. Geerling JC, Kawata M, Loewy AD (2006b) Aldosterone-sensitive neurons in the rat central nervous system. J Comp Neurol 494(3):515–527Google Scholar
  39. Geerling JC, Chimenti PC, Loewy AD (2008) Phox2b expression in the aldosterone-sensitive HSD2 neurons of the NTS. Brain Res 1226:82–88Google Scholar
  40. Geerling JC, Shin JW, Chimenti PC, Loewy AD (2010) Paraventricular hypothalamic nucleus: axonal projections to the brainstem. J Comp Neurol 518(9):1460–1499Google Scholar
  41. Geerling JC, Stein MK, Miller RL, Shin JW, Gray PA, Loewy AD (2011) FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation. Brain Res 1375:19–27Google Scholar
  42. Gomez-Sanchez EP (1986) Intracerebroventricular infusion of aldosterone induces hypertension in rats. Endocrinology 118(2):819–823Google Scholar
  43. Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, Nowak NJ, Joyner A, Leblanc G, Hatten ME, Heintz N (2003) A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425(6961):917–925Google Scholar
  44. Gonzalez AD, Wang G, Waters EM, Gonzales KL, Speth RC, Van Kempen TA, Marques-Lopes J, Young CN, Butler SD, Davisson RL, Iadecola C, Pickel VM, Pierce JP, Milner TA (2012) Distribution of angiotensin type 1a receptor-containing cells in the brains of bacterial artificial chromosome transgenic mice. Neuroscience 226:489–509Google Scholar
  45. Grippo AJ, Moffitt JA, Beltz TG, Johnson AK (2006) Reduced hedonic behavior and altered cardiovascular function induced by mild sodium depletion in rats. Behav Neurosci 120(5):1133–1143Google Scholar
  46. Gross PM, Wall KM, Pang JJ, Shaver SW, Wainman DS (1990) Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius. Am J Physiol 259(6 Pt 2):R1131–R1138Google Scholar
  47. Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7(5):335–346Google Scholar
  48. Haque M, Wilson R, Sharma K, Mills NJ, Teruyama R (2015) Localisation of 11beta-hydroxysteroid dehydrogenase type 2 in mineralocorticoid receptor expressing magnocellular neurosecretory neurones of the rat supraoptic and paraventricular nuclei. J Neuroendocrinol 27(11):835–849Google Scholar
  49. Haskell-Luevano C, Monck EK (2001) Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor. Regul Pept 99(1):1–7Google Scholar
  50. Herbert H, Saper CB (1990) Cholecystokinin-, galanin-, and corticotropin-releasing factor-like immunoreactive projections from the nucleus of the solitary tract to the parabrachial nucleus in the rat. J Comp Neurol 293(4):581–598Google Scholar
  51. Hlavacova N, Jezova D (2008) Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior. Horm Behav 54(1):90–97Google Scholar
  52. Hlavacova N, Wes PD, Ondrejcakova M, Flynn ME, Poundstone PK, Babic S, Murck H, Jezova D (2012) Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder. Int J Neuropsychopharmacol 15(2):247–265Google Scholar
  53. Holmes MC, Sangra M, French KL, Whittle IR, Paterson J, Mullins JJ, Seckl JR (2006) 11beta-Hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids. Neuroscience 137(3):865–873Google Scholar
  54. Jarvie BC, Palmiter RD (2017) HSD2 neurons in the hindbrain drive sodium appetite. Nat Neurosci 20(2):167–169Google Scholar
  55. Jellinck PH, Monder C, McEwen BS, Sakai RR (1993) Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues. J Steroid Biochem Mol Biol 46(2):209–213Google Scholar
  56. Kang BJ, Chang DA, Mackay DD, West GH, Moreira TS, Takakura AC, Gwilt JM, Guyenet PG, Stornetta RL (2007) Central nervous system distribution of the transcription factor Phox2b in the adult rat. J Comp Neurol 503(5):627–641Google Scholar
  57. Kawai Y (2018) Differential ascending projections from the male rat caudal nucleus of the tractus solitarius: an interface between local microcircuits and global macrocircuits. Front Neuroanat 12:63Google Scholar
  58. Kawai Y, Senba E (1996) Organization of excitatory and inhibitory local networks in the caudal nucleus of tractus solitarius of rats revealed in in vitro slice preparation. J Comp Neurol 373(3):309–321Google Scholar
  59. Koneru B, Bathina CS, Cherry BH, Mifflin SW (2014) Mineralocorticoid receptor in the NTS stimulates saline intake during fourth ventricular infusions of aldosterone. Am J Physiol Regul Integr Comp Physiol 306(1):R61–R66Google Scholar
  60. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, Maratos-Flier E, Roth BL, Lowell BB (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121(4):1424–1428Google Scholar
  61. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, Vong L, Pei H, Watabe-Uchida M, Uchida N, Liberles SD, Lowell BB (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507(7491):238–242Google Scholar
  62. Lesman-Leegte I, Jaarsma T, Sanderman R, Linssen G, van Veldhuisen DJ (2006) Depressive symptoms are prominent among elderly hospitalised heart failure patients. Eur J Heart Fail 8(6):634–640Google Scholar
  63. Loewy A, Spyer K (1990) Central regulation of autonomic functions. Oxford University Press, New YorkGoogle Scholar
  64. Luquet S, Perez FA, Hnasko TS, Palmiter RD (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310(5748):683–685Google Scholar
  65. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD, Hawrylycz MJ, Jones AR, Lein ES, Zeng H (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13(1):133–140Google Scholar
  66. Malinow KC, Lion JR (1979) Hyperaldosteronism (Conn’s disease) presenting as depression. J Clin Psychiatry 40(8):358–359Google Scholar
  67. Matsuda T, Hiyama TY, Niimura F, Matsusaka T, Fukamizu A, Kobayashi K, Kobayashi K, Noda M (2017) Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ. Nat Neurosci 20(2):230–241Google Scholar
  68. McCance RA (1936) Experimental human salt deficiency. Lancet 1:823–830Google Scholar
  69. McKinley MJ, Badoer E, Oldfield BJ (1992) Intravenous angiotensin II induces Fos-immunoreactivity in circumventricular organs of the lamina terminalis. Brain Res 594(2):295–300Google Scholar
  70. Morris MJ, Na ES, Grippo AJ, Johnson AK (2006) The effects of deoxycorticosterone-induced sodium appetite on hedonic behaviors in the rat. Behav Neurosci 120(3):571–579Google Scholar
  71. Murck H, Buttner M, Kircher T, Konrad C (2014) Genetic, molecular and clinical determinants for the involvement of aldosterone and its receptors in major depression. Nephron Physiol 128(1–2):17–25Google Scholar
  72. Naray-Fejes-Toth A, Fejes-Toth G (2007) Novel mouse strain with Cre recombinase in 11beta-hydroxysteroid dehydrogenase-2-expressing cells. Am J Physiol Renal Physiol 292(1):F486–F494Google Scholar
  73. Naray-Fejes-Toth A, Colombowala IK, Fejes-Toth G (1998) The role of 11beta-hydroxysteroid dehydrogenase in steroid hormone specificity. J Steroid Biochem Mol Biol 65(1–6):311–316Google Scholar
  74. Nijenhuis WA, Oosterom J, Adan RA (2001) AgRP(83–132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol Endocrinol 15(1):164–171Google Scholar
  75. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278(5335):135–138Google Scholar
  76. Palmiter RD (2018) The parabrachial nucleus: CGRP neurons function as a general alarm. Trends Neurosci 41(5):280–293Google Scholar
  77. Pardridge WM, Mietus LJ (1979) Transport of steroid hormones through the rat blood-brain barrier. Primary role of albumin-bound hormone. J Clin Invest 64(1):145–154Google Scholar
  78. Parvizi J, Damasio A (2001) Consciousness and the brainstem. Cognition 79(1–2):135–160Google Scholar
  79. Price JL, Drevets WC (2012) Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci 16(1):61–71Google Scholar
  80. Reincke M (2018) Anxiety, depression, and impaired quality of life in primary aldosteronism: why we shouldn’t ignore it! J Clin Endocrinol Metab 103(1):1–4Google Scholar
  81. Resch JM, Fenselau H, Madara JC, Wu C, Campbell JN, Lyubetskaya A, Dawes BA, Tsai LT, Li MM, Livneh Y, Ke Q, Kang PM, Fejes-Toth G, Naray-Fejes-Toth A, Geerling JC, Lowell BB (2017) Aldosterone-sensing neurons in the NTS exhibit state-dependent pacemaker activity and drive sodium appetite via synergy with angiotensin II signaling. Neuron 96(1):190–206 (e197) Google Scholar
  82. Robson AC, Leckie CM, Seckl JR, Holmes MC (1998) 11 Beta-hydroxysteroid dehydrogenase type 2 in the postnatal and adult rat brain. Brain Res Mol Brain Res 61(1–2):1–10Google Scholar
  83. Roland BL, Li KX, Funder JW (1995) Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain. Endocrinology 136(10):4697–4700Google Scholar
  84. Rowland NE, Fregly MJ (1988) Characteristics of thirst and sodium appetite in mice (Mus musculus). Behav Neurosci 102(6):969–974Google Scholar
  85. Rutledge T, Reis VA, Linke SE, Greenberg BH, Mills PJ (2006) Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes. J Am Coll Cardiol 48(8):1527–1537Google Scholar
  86. Sakai RR, Ma LY, Zhang DM, McEwen BS, Fluharty SJ (1996) Intracerebral administration of mineralocorticoid receptor antisense oligonucleotides attenuate adrenal steroid-induced salt appetite in rats. Neuroendocrinology 64(6):425–429Google Scholar
  87. Sakai RR, McEwen BS, Fluharty SJ, Ma LY (2000) The amygdala: site of genomic and nongenomic arousal of aldosterone-induced sodium intake. Kidney Int 57(4):1337–1345Google Scholar
  88. Saper CB (2016) The house alarm. Cell Metab 23(5):754–755Google Scholar
  89. Sawchenko PE, Brown ER, Chan RK, Ericsson A, Li HY, Roland BL, Kovacs KJ (1996) The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res 107:201–222Google Scholar
  90. Sequeira SM, Geerling JC, Loewy AD (2006) Local inputs to aldosterone-sensitive neurons of the nucleus tractus solitarius. Neuroscience 141(4):1995–2005Google Scholar
  91. Shields AD, Wang Q, Winder DG (2009) alpha2A-adrenergic receptors heterosynaptically regulate glutamatergic transmission in the bed nucleus of the stria terminalis. Neuroscience 163(1):339–351Google Scholar
  92. Shin JW, Geerling JC, Loewy AD (2008) Inputs to the ventrolateral bed nucleus of the stria terminalis. J Comp Neurol 511(5):628–657Google Scholar
  93. Shin JW, Geerling JC, Loewy AD (2009) Vagal innervation of the aldosterone-sensitive HSD2 neurons in the NTS. Brain Res 1249:135–147Google Scholar
  94. Shin JW, Geerling JC, Stein MK, Miller RL, Loewy AD (2011) FoxP2 brainstem neurons project to sodium appetite regulatory sites. J Chem Neuroanat 42(1):1–23Google Scholar
  95. Simpson JB, Routtenberg A (1978) Subfornical organ: a dipsogenic site of action of angiotensin II. Science 201(4353):379–381Google Scholar
  96. Song K, Allen AM, Paxinos G, Mendelsohn FA (1992) Mapping of angiotensin II receptor subtype heterogeneity in rat brain. J Comp Neurol 316(4):467–484Google Scholar
  97. Sonino N, Fallo F, Fava GA (2006) Psychological aspects of primary aldosteronism. Psychother Psychosom 75(5):327–330Google Scholar
  98. Sonino N, Tomba E, Genesia ML, Bertello C, Mulatero P, Veglio F, Fava GA, Fallo F (2011) Psychological assessment of primary aldosteronism: a controlled study. J Clin Endocrinol Metab 96(6):E878–E883Google Scholar
  99. Stornetta RL, Hawelu-Johnson CL, Guyenet PG, Lynch KR (1988) Astrocytes synthesize angiotensinogen in brain. Science 242(4884):1444–1446Google Scholar
  100. Sunn N, McKinley MJ, Oldfield BJ (2003) Circulating angiotensin II activates neurones in circumventricular organs of the lamina terminalis that project to the bed nucleus of the stria terminalis. J Neuroendocrinol 15(8):725–731Google Scholar
  101. Szabo NE, da Silva RV, Sotocinal SG, Zeilhofer HU, Mogil JS, Kania A (2015) Hoxb8 intersection defines a role for Lmx1b in excitatory dorsal horn neuron development, spinofugal connectivity, and nociception. J Neurosci 35(13):5233–5246Google Scholar
  102. Terenzi MG, Ingram CD (1995) A combined immunocytochemical and retrograde tracing study of noradrenergic connections between the caudal medulla and bed nuclei of the stria terminalis. Brain Res 672(1–2):289–297Google Scholar
  103. Tindell AJ, Smith KS, Pecina S, Berridge KC, Aldridge JW (2006) Ventral pallidum firing codes hedonic reward: when a bad taste turns good. J Neurophysiol 96(5):2399–2409Google Scholar
  104. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB (2008) Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11(9):998–1000Google Scholar
  105. Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R (1992) Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem 267(34):24248–24252Google Scholar
  106. Uhr M, Holsboer F, Muller MB (2002) Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins. J Neuroendocrinol 14(9):753–759Google Scholar
  107. Velema MS, de Nooijer AH, Burgers VWG, Hermus A, Timmers H, Lenders JWM, Husson O, Deinum J (2017) Health-related quality of life and mental health in primary aldosteronism: a systematic review. Horm Metab Res 49(12):943–950Google Scholar
  108. Verstegen AMJ, Vanderhorst V, Gray PA, Zeidel ML, Geerling JC (2017) Barrington’s nucleus: neuroanatomic landscape of the mouse “pontine micturition center”. J Comp NeurolGoogle Scholar
  109. Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463(1–3):199–216Google Scholar
  110. Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137(7):1225–1234Google Scholar
  111. Zardetto-Smith AM, Beltz TG, Johnson AK (1994) Role of the central nucleus of the amygdala and bed nucleus of the stria terminalis in experimentally-induced salt appetite. Brain Res 645(1–2):123–134Google Scholar
  112. Zeisel A, Hochgerner H, Lonnerberg P, Johnsson A, Memic F, van der Zwan J, Haring M, Braun E, Borm LE, La Manno G, Codeluppi S, Furlan A, Lee K, Skene N, Harris KD, Hjerling-Leffler J, Arenas E, Ernfors P, Marklund U, Linnarsson S (2018) Molecular architecture of the mouse nervous system. Cell 174(4):999–1014 (e1022) Google Scholar
  113. Zhang ZH, Kang YM, Yu Y, Wei SG, Schmidt TJ, Johnson AK, Felder RB (2006) 11beta-hydroxysteroid dehydrogenase type 2 activity in hypothalamic paraventricular nucleus modulates sympathetic excitation. Hypertension 48(1):127–133Google Scholar

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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