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Aldosterone-sensitive HSD2 neurons in mice

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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.

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Notes

  1. In preparing this manuscript, we also found evidence of Ai75 neurotoxicity in Slc17a7-IRES3-Cre mice (http://connectivity.brain-map.org/transgenic/experiment/304698566), which appears to be age-related and specific to regions that express that Cre-driver gene (hippocampus, cerebral cortex).

References

  • Aponte Y, Atasoy D, Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14(3):351–355

    Article  CAS  PubMed  Google Scholar 

  • Arriza JL, Simerly RB, Swanson LW, Evans RM (1988) The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1(9):887–900

    Article  CAS  PubMed  Google Scholar 

  • 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 9:91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 877:486–498

    Article  CAS  PubMed  Google Scholar 

  • Bard P (1928) A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system. Am J Physiol 84(3):490–515

    Article  Google Scholar 

  • Betley JN, Cao ZF, Ritola KD, Sternson SM (2013) Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155(6):1337–1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):245–263

    Article  CAS  PubMed  Google Scholar 

  • Chang RB, Strochlic DE, Williams EK, Umans BD, Liberles SD (2015) Vagal sensory neuron subtypes that differentially control breathing. Cell 161(3):622–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):5670–5680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):107–111

    Article  CAS  PubMed  Google Scholar 

  • Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 3(8):655–666

    Article  CAS  PubMed  Google Scholar 

  • 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):341–355

    Article  CAS  PubMed  Google Scholar 

  • 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)

  • Denton DA, Sabine JR (1961) The selective appetite for Na ions shown by Na ion-deficient sheep. J Physiol 157:97–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):2570–2580

    Article  CAS  PubMed  Google Scholar 

  • Dong HW (2008) Allen reference atlas: a digital color brain atlas of the C57Black/6J male mouse. Wiley. ix, Hoboken, 366 p. p

    Google Scholar 

  • 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):430–455

    Article  CAS  PubMed  Google Scholar 

  • 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):657–668

    Article  CAS  PubMed  Google Scholar 

  • Epstein AN (1982) Mineralocorticoids and cerebral angiotensin may act together to produce sodium appetite. Peptides 3(3):493–494

    Article  CAS  PubMed  Google Scholar 

  • 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):8678–8687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1360–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):721–726

    Article  CAS  PubMed  Google Scholar 

  • 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):746–758

    Article  CAS  PubMed  Google Scholar 

  • 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–R259

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (2013) Paxinos and Franklin’s The mouse brain in stereotaxic coordinates. Academic Press, Amsterdam

    Google Scholar 

  • 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):5264–5268

    Article  CAS  PubMed  Google Scholar 

  • Funder JW, Pearce PT, Smith R, Smith AI (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242(4878):583–585

    Article  CAS  PubMed  Google Scholar 

  • 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):863–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):646–657

    Article  PubMed  PubMed Central  Google Scholar 

  • Geerling JC, Loewy AD (2006b) Aldosterone-sensitive neurons in the nucleus of the solitary tract: efferent projections. J Comp Neurol 497(2):223–250

    Article  CAS  PubMed  Google Scholar 

  • Geerling JC, Loewy AD (2006c) Aldosterone-sensitive NTS neurons are inhibited by saline ingestion during chronic mineralocorticoid treatment. Brain Res 1115(1):54–64

    Article  CAS  PubMed  Google Scholar 

  • 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)

    Article  CAS  PubMed  Google Scholar 

  • 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–R1348

    Article  CAS  PubMed  Google Scholar 

  • 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):379–403

    Article  CAS  PubMed  Google Scholar 

  • Geerling JC, Loewy AD (2008) Central regulation of sodium appetite. Exp Physiol 93(2):177–209

    Article  CAS  PubMed  Google Scholar 

  • Geerling JC, Loewy AD (2009) Aldosterone in the brain. Am J Physiol Renal Physiol 297(3):F559–F576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geerling JC, Engeland WC, Kawata M, Loewy AD (2006a) Aldosterone target neurons in the nucleus tractus solitarius drive sodium appetite. J Neurosci 26(2):411–417

    Article  CAS  PubMed  Google Scholar 

  • Geerling JC, Kawata M, Loewy AD (2006b) Aldosterone-sensitive neurons in the rat central nervous system. J Comp Neurol 494(3):515–527

    Article  PubMed  Google Scholar 

  • Geerling JC, Chimenti PC, Loewy AD (2008) Phox2b expression in the aldosterone-sensitive HSD2 neurons of the NTS. Brain Res 1226:82–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geerling JC, Shin JW, Chimenti PC, Loewy AD (2010) Paraventricular hypothalamic nucleus: axonal projections to the brainstem. J Comp Neurol 518(9):1460–1499

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 1375:19–27

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Sanchez EP (1986) Intracerebroventricular infusion of aldosterone induces hypertension in rats. Endocrinology 118(2):819–823

    Article  CAS  PubMed  Google Scholar 

  • 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):917–925

    Article  CAS  PubMed  Google Scholar 

  • 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 226:489–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1133–1143

    Article  CAS  PubMed  Google Scholar 

  • 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–R1138

    CAS  PubMed  Google Scholar 

  • Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7(5):335–346

    Article  CAS  Google Scholar 

  • 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):835–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1–7

    Article  CAS  PubMed  Google Scholar 

  • 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):581–598

    Article  CAS  PubMed  Google Scholar 

  • Hlavacova N, Jezova D (2008) Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior. Horm Behav 54(1):90–97

    Article  CAS  PubMed  Google Scholar 

  • 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):247–265

    Article  CAS  PubMed  Google Scholar 

  • 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):865–873

    Article  CAS  PubMed  Google Scholar 

  • Jarvie BC, Palmiter RD (2017) HSD2 neurons in the hindbrain drive sodium appetite. Nat Neurosci 20(2):167–169

    Article  CAS  PubMed  Google Scholar 

  • 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):209–213

    Article  CAS  PubMed  Google Scholar 

  • 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):627–641

    Article  CAS  PubMed  Google Scholar 

  • 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 12:63

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):309–321

    Article  CAS  PubMed  Google Scholar 

  • 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–R66

    Article  CAS  PubMed  Google Scholar 

  • 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):1424–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):238–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):634–640

    Article  PubMed  Google Scholar 

  • Loewy A, Spyer K (1990) Central regulation of autonomic functions. Oxford University Press, New York

    Google Scholar 

  • 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):683–685

    Article  CAS  PubMed  Google Scholar 

  • 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):133–140

    Article  CAS  PubMed  Google Scholar 

  • Malinow KC, Lion JR (1979) Hyperaldosteronism (Conn’s disease) presenting as depression. J Clin Psychiatry 40(8):358–359

    CAS  PubMed  Google Scholar 

  • 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):230–241

    Article  CAS  PubMed  Google Scholar 

  • McCance RA (1936) Experimental human salt deficiency. Lancet 1:823–830

    Article  Google Scholar 

  • McKinley MJ, Badoer E, Oldfield BJ (1992) Intravenous angiotensin II induces Fos-immunoreactivity in circumventricular organs of the lamina terminalis. Brain Res 594(2):295–300

    Article  CAS  PubMed  Google Scholar 

  • 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):571–579

    Article  CAS  PubMed  Google Scholar 

  • 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):17–25

    Article  CAS  PubMed  Google Scholar 

  • 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–F494

    Article  CAS  PubMed  Google Scholar 

  • 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):311–316

    Article  CAS  PubMed  Google Scholar 

  • 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):164–171

    CAS  PubMed  Google Scholar 

  • 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):135–138

    Article  CAS  PubMed  Google Scholar 

  • Palmiter RD (2018) The parabrachial nucleus: CGRP neurons function as a general alarm. Trends Neurosci 41(5):280–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):145–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parvizi J, Damasio A (2001) Consciousness and the brainstem. Cognition 79(1–2):135–160

    Article  CAS  Google Scholar 

  • Price JL, Drevets WC (2012) Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci 16(1):61–71

    Article  PubMed  Google Scholar 

  • 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):1–4

    Article  PubMed  Google Scholar 

  • 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1–10

    Article  CAS  PubMed  Google Scholar 

  • Roland BL, Li KX, Funder JW (1995) Hybridization histochemical localization of 11 beta-hydroxysteroid dehydrogenase type 2 in rat brain. Endocrinology 136(10):4697–4700

    Article  CAS  PubMed  Google Scholar 

  • Rowland NE, Fregly MJ (1988) Characteristics of thirst and sodium appetite in mice (Mus musculus). Behav Neurosci 102(6):969–974

    Article  CAS  PubMed  Google Scholar 

  • 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):1527–1537

    Article  Google Scholar 

  • 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):425–429

    Article  CAS  PubMed  Google Scholar 

  • 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):1337–1345

    Article  CAS  PubMed  Google Scholar 

  • Saper CB (2016) The house alarm. Cell Metab 23(5):754–755

    Article  CAS  PubMed  Google Scholar 

  • 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 107:201–222

    Article  CAS  PubMed  Google Scholar 

  • Sequeira SM, Geerling JC, Loewy AD (2006) Local inputs to aldosterone-sensitive neurons of the nucleus tractus solitarius. Neuroscience 141(4):1995–2005

    Article  CAS  PubMed  Google Scholar 

  • 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):339–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin JW, Geerling JC, Loewy AD (2008) Inputs to the ventrolateral bed nucleus of the stria terminalis. J Comp Neurol 511(5):628–657

    Article  PubMed  PubMed Central  Google Scholar 

  • Shin JW, Geerling JC, Loewy AD (2009) Vagal innervation of the aldosterone-sensitive HSD2 neurons in the NTS. Brain Res 1249:135–147

    Article  CAS  PubMed  Google Scholar 

  • 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):1–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simpson JB, Routtenberg A (1978) Subfornical organ: a dipsogenic site of action of angiotensin II. Science 201(4353):379–381

    Article  CAS  PubMed  Google Scholar 

  • Song K, Allen AM, Paxinos G, Mendelsohn FA (1992) Mapping of angiotensin II receptor subtype heterogeneity in rat brain. J Comp Neurol 316(4):467–484

    Article  CAS  PubMed  Google Scholar 

  • Sonino N, Fallo F, Fava GA (2006) Psychological aspects of primary aldosteronism. Psychother Psychosom 75(5):327–330

    Article  PubMed  Google Scholar 

  • 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–E883

    Article  CAS  Google Scholar 

  • Stornetta RL, Hawelu-Johnson CL, Guyenet PG, Lynch KR (1988) Astrocytes synthesize angiotensinogen in brain. Science 242(4884):1444–1446

    Article  CAS  PubMed  Google Scholar 

  • 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):725–731

    Article  CAS  PubMed  Google Scholar 

  • 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):5233–5246

    Article  CAS  PubMed  Google Scholar 

  • 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):289–297

    Article  CAS  PubMed  Google Scholar 

  • 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):2399–2409

    Article  PubMed  Google Scholar 

  • 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):998–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):24248–24252

    CAS  PubMed  Google Scholar 

  • 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):753–759

    Article  CAS  PubMed  Google Scholar 

  • 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):943–950

    Article  CAS  PubMed  Google Scholar 

  • Verstegen AMJ, Vanderhorst V, Gray PA, Zeidel ML, Geerling JC (2017) Barrington’s nucleus: neuroanatomic landscape of the mouse “pontine micturition center”. J Comp Neurol

  • 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):199–216

    Article  CAS  PubMed  Google Scholar 

  • Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137(7):1225–1234

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):123–134

    Article  CAS  PubMed  Google Scholar 

  • 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):127–133

    Article  CAS  PubMed  Google Scholar 

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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).

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Authors and Affiliations

  1. Department of Neurology, University of Iowa, PBDB 1320, 169 Newton Rd., Iowa City, IA, 52246, USA

    Silvia Gasparini, Sowmya V. Narayan, Lila Peltekian, Gabrielle N. Iverson, Samyukta Karthik & Joel C. Geerling

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, USA

    Jon M. Resch

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  1. Silvia Gasparini
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  3. Sowmya V. Narayan
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Correspondence to Joel C. Geerling.

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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.

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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)

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)

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)

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)

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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Gasparini, S., Resch, J.M., Narayan, S.V. et al. Aldosterone-sensitive HSD2 neurons in mice. Brain Struct Funct 224, 387–417 (2019). https://doi.org/10.1007/s00429-018-1778-y

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