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Assessing Behavioural Effects of Chronic HPA Axis Activation Using Conditional CRH-Overexpressing Mice

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Abstract

The corticotropin-releasing hormone (CRH) and its cognate receptors have been implicated in the pathophysiology of stress-related disorders. Hypersecretion of central CRH and elevated glucocorticoid levels, as a consequence of impaired feedback control, have been shown to accompany mood and anxiety disorders. However, a clear discrimination of direct effects of centrally hypersecreted CRH from those resulting from HPA axis activation has been difficult. Applying a conditional strategy, we have generated two conditional CRH-overexpressing mouse lines: CRH-COE Del mice overexpress CRH throughout the body, while CRH-COE APit mice selectively overexpress CRH in the anterior and intermediate lobe of the pituitary. Both mouse lines show increased basal plasma corticosterone levels and consequently develop signs of Cushing’s syndrome. However, while mice ubiquitously overexpressing CRH exhibited increased anxiety-related behaviour, overexpression of CRH in the pituitary did not produce alterations in emotional behaviour. These results suggest that chronic hypercorticosteroidism alone is not sufficient to alter anxiety-related behaviour but rather that central CRH hyperdrive on its own or in combination with elevated glucocorticoids is responsible for the increase in anxiety-related behaviour. In conclusion, the generated mouse lines represent valuable animal models to study the consequences of chronic CRH overproduction and HPA axis activation.

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References

  • Akagi K, Sandig V, Vooijs M, Van der Valk M, Giovannini M, Strauss M, Berns A (1997) Cre-mediated somatic site-specific recombination in mice. Nucl Acids Res 25:1766–1773

    Article  PubMed  CAS  Google Scholar 

  • Andreano JM, Cahill L (2009) Sex influences on the neurobiology of learning and memory. Learn Mem 16:248–266

    Article  PubMed  Google Scholar 

  • Ardayfio P, Kim KS (2006) Anxiogenic-like effect of chronic corticosterone in the light–dark emergence task in mice. Behav Neurosci 120:249–256

    Article  PubMed  CAS  Google Scholar 

  • Atkinson HC, Leggett JD, Wood SA, Castrique ES, Kershaw YM, Lightman SL (2010) Regulation of the hypothalamic-pituitary-adrenal axis circadian rhythm by endocannabinoids is sexually diergic. Endocrinology 151:3720–3727

    Article  PubMed  CAS  Google Scholar 

  • Brotto LA, Gorzalka BB, Barr AM (2001) Paradoxical effects of chronic corticosterone on forced swim behaviours in aged male and female rats. Eur J Pharmacol 424:203–209

    Article  PubMed  CAS  Google Scholar 

  • Brown ES, Suppes T (1998) Mood symptoms during corticosteroid therapy: a review. Harv Rev Psychiatry 5:239–246

    Article  PubMed  CAS  Google Scholar 

  • Celano CM, Freudenreich O, Fernandez-Robles C, Stern TA, Caro MA, Huffman JC (2011) Depressogenic effects of medications: a review. Dialogues. Clin Neurosci 13:109–125

    Google Scholar 

  • Coste SC, Murray SE, Stenzel-Poore MP (2001) Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress. Peptides 22:733–741

    Article  PubMed  CAS  Google Scholar 

  • David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493

    Article  PubMed  CAS  Google Scholar 

  • de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475

    Article  PubMed  Google Scholar 

  • Deussing JM, Wurst W (2005) Dissecting the genetic effect of the CRH system on anxiety and stress-related behaviour. Comptes Rendus Biologies 328:199–212

    Article  PubMed  CAS  Google Scholar 

  • Dirks A, Groenink L, Verdouw MP, Schipholt M, Jvd Gugten, Hijzen T, Olivier B (2001) Behavioural analysis of transgenic mice overexpressing corticotropin-releasing hormone in paradigms emulating aspects of stress, anxiety, and depression. Int J Comp Psychology 16:123–135

    Google Scholar 

  • Dirks A, Groenink L, Bouwknecht JA, Hijzen TH, Van Der GJ, Ronken E, Verbeek JS, Veening JG, Dederen PJ, Korosi A, Schoolderman LF, Roubos EW, Olivier B (2002a) Overexpression of corticotropin-releasing hormone in transgenic mice and chronic stress-like autonomic and physiological alterations. Eur J Neurosci 16:1751–1760

    Article  PubMed  Google Scholar 

  • Dirks A, Groenink L, Schipholt MI, Van Der GJ, Hijzen TH, Geyer MA, Olivier B (2002b) Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone. Biol Psychiatry 51:583–590

    Article  PubMed  CAS  Google Scholar 

  • Drossopoulou G, Antoniou K, Kitraki E, Papathanasiou G, Papalexi E, Dalla C, Papadopoulou-Daifoti Z (2004) Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats. Neuroscience 126:849–857

    Article  PubMed  CAS  Google Scholar 

  • Erdmann G, Schütz G, Berger S (2007) Inducible gene inactivation in neurons of the adult mouse forebrain. BMC Neurosci 8:63

    Article  PubMed  Google Scholar 

  • Flandreau EI, Ressler KJ, Owens MJ, Nemeroff CB (2011) Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behaviorial anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus. Psychoneuroendocrinology

  • Friess E, Bardeleben V, Wiedemann K, Lauer CJ, Holsboer F (1994) Effects of pulsatile cortisol infusion on sleep-EEG and nocturnal growth hormone release in healthy men. J Sleep Res 3:73–79

    Article  PubMed  Google Scholar 

  • Gallagher JP, Orozco-Cabal LF, Liu J, Shinnick-Gallagher P (2008) Synaptic physiology of central CRH system. Eur J Pharmacol 583:215–225

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Caceres C, Lagunas N, Calmarza-Font I, Azcoitia I, Diz-Chaves Y, Garcia-Segura LM, Baquedano E, Frago LM, Argente J, Chowen JA (2010) Gender differences in the long-term effects of chronic prenatal stress on the HPA axis and hypothalamic structure in rats. Psychoneuroendocrinology 35:1525–1535

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Lecumberri C, Ambrosio E (2000) Differential effect of low doses of intracerebroventricular corticotropin-releasing factor in forced swimming test. Pharmacol Biochem Behav 67:519–525

    Article  PubMed  CAS  Google Scholar 

  • Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, Taylor JR (2008) Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry 63:353–359

    Article  PubMed  CAS  Google Scholar 

  • Gregus A, Wintink AJ, Davis AC, Kalynchuk LE (2005) Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res 156:105–114

    Article  PubMed  CAS  Google Scholar 

  • Groenink L, Dirks A, Verdouw PM, Schipholt M, Veening JG, Van Der GJ, Olivier B (2002) HPA axis dysregulation in mice overexpressing corticotropin releasing hormone. Biol Psychiatry 51:875–881

    Article  PubMed  CAS  Google Scholar 

  • Groenink L, Pattij T, De JR, Van Der GJ, Oosting RS, Dirks A, Olivier B (2003) 5-HT1A receptor knockout mice and mice overexpressing corticotropin-releasing hormone in models of anxiety. Eur J Pharmacol 463:185–197

    Article  PubMed  CAS  Google Scholar 

  • Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang XD, Wolf M, Hausch F, Rein T, Schmidt U, Touma C, Cheung-Flynn J, Cox MB, Smith DF, Holsboer F, Muller MB, Schmidt MV (2011) The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology 62:332–339

    Article  PubMed  Google Scholar 

  • Heinrichs SC, Richard D (1999) The role of corticotropin-releasing factor and urocortin in the modulation of ingestive behavior. Neuropeptides 33:350–359

    Article  PubMed  CAS  Google Scholar 

  • Heinrichs SC, Menzaghi F, Pich EM, Hauger RL, Koob GF (1993) Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y. Brain Res 611:18–24

    Article  PubMed  CAS  Google Scholar 

  • Heinrichs SC, Min H, Tamraz S, Carmouche M, Boehme SA, Vale WW (1997) Anti-sexual and anxiogenic behavioral consequences of corticotropin-releasing factor overexpression are centrally mediated. Psychoneuroendocrinology 22:215–224

    Article  PubMed  CAS  Google Scholar 

  • Het S, Wolf OT (2007) Mood changes in response to psychosocial stress in healthy young women: effects of pretreatment with cortisol. Behav Neurosci 121:11–20

    Article  PubMed  CAS  Google Scholar 

  • Holsboer F (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 33:181–214

    Article  PubMed  CAS  Google Scholar 

  • Kimura M, Muller-Preuss P, Lu A, Wiesner E, Flachskamm C, Wurst W, Holsboer F, Deussing JM (2010) Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. Mol Psychiatry 15:154–165

    Article  PubMed  CAS  Google Scholar 

  • Kolber BJ, Boyle MP, Wieczorek L, Kelley CL, Onwuzurike CC, Nettles SA, Vogt SK, Muglia LJ (2010) Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J Neurosci 30:2571–2581

    Article  PubMed  CAS  Google Scholar 

  • Lowy MT, Reder AT, Antel JP, Meltzer HY (1984) Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone. Am J Psychiatry 141:1365–1370

    PubMed  CAS  Google Scholar 

  • Lu A, Steiner MA, Whittle N, Vogl AM, Walser SM, Ableitner M, Refojo D, Ekker M, Rubenstein JL, Stalla GK, Singewald N, Holsboer F, Wotjak CT, Wurst W, Deussing JM (2008) Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol Psychiatry 13:1028–1042

    Article  PubMed  CAS  Google Scholar 

  • Menzaghi F, Heinrichs SC, Pich EM, Tilders FJ, Koob GF (1993) Functional impairment of hypothalamic corticotropin-releasing factor neurons with immunotargeted toxins enhances food intake induced by neuropeptide Y. Brain Res 618:76–82

    Article  PubMed  CAS  Google Scholar 

  • Muller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, Kormann MS, Droste SK, Kuhn R, Reul JM, Holsboer F, Wurst W (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6:1100–1107

    Article  PubMed  Google Scholar 

  • Murray F, Smith DW, Hutson PH (2008) Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice. Eur J Pharmacol 583:115–127

    Article  PubMed  CAS  Google Scholar 

  • Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226:1342–1344

    Article  PubMed  CAS  Google Scholar 

  • Nieuwenhuizen AG, Rutters F (2008) The hypothalamic–pituitary–adrenal-axis in the regulation of energy balance. Physiol Behav 94:169–177

    Article  PubMed  CAS  Google Scholar 

  • Peeters F, Nicolson NA, Berkhof J (2004) Levels and variability of daily life cortisol secretion in major depression. Psychiatry Res 126:1–13

    Article  PubMed  CAS  Google Scholar 

  • Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom D, Schutz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333:1903–1907

    Article  PubMed  CAS  Google Scholar 

  • Reuter M (2002) Impact of cortisol on emotions under stress and nonstress conditions: a pharmacopsychological approach. Neuropsychobiology 46:41–48

    Article  PubMed  CAS  Google Scholar 

  • Rhees RW, Al-Saleh HN, Kinghorn EW, Fleming DE, Lephart ED (1999) Relationship between sexual behavior and sexually dimorphic structures in the anterior hypothalamus in control and prenatally stressed male rats. Brain Res Bull 50:193–199

    Article  PubMed  CAS  Google Scholar 

  • Romanowski CP, Fenzl T, Flachskamm C, Wurst W, Holsboer F, Deussing JM, Kimura M (2010) Central deficiency of corticotropin-releasing hormone receptor type 1 (CRH-R1) abolishes effects of CRH on NREM but not on REM sleep in mice. Sleep 33:427–436

    PubMed  Google Scholar 

  • Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671

    PubMed  CAS  Google Scholar 

  • Seale JV, Wood SA, Atkinson HC, Bate E, Lightman SL, Ingram CD, Jessop DS, Harbuz MS (2004) Gonadectomy reverses the sexually diergic patterns of circadian and stress-induced hypothalamic-pituitary-adrenal axis activity in male and female rats. J Neuroendocrinol 16:516–524

    Article  PubMed  CAS  Google Scholar 

  • Stengel A, Goebel M, Million M, Stenzel-Poore MP, Kobelt P, Monnikes H, Tache Y, Wang L (2009) Corticotropin-releasing factor-overexpressing mice exhibit reduced neuronal activation in the arcuate nucleus and food intake in response to fasting. Endocrinology 150:153–160

    Article  PubMed  CAS  Google Scholar 

  • Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W (1992) Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 130:3378–3386

    Article  PubMed  CAS  Google Scholar 

  • Stenzel-Poore MP, Heinrichs SC, Rivest S, Koob GF, Vale WW (1994) Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci 14:2579–2584

    PubMed  CAS  Google Scholar 

  • Stone EA, Lin Y (2008) An anti-immobility effect of exogenous corticosterone in mice. Eur J Pharmacol 580:135–142

    Article  PubMed  CAS  Google Scholar 

  • Tezval H, Jahn O, Todorovic C, Sasse A, Eckart K, Spiess J (2004) Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model. Proc Natl Acad Sci USA 101:9468–9473

    Article  PubMed  CAS  Google Scholar 

  • Touma C, Bunck M, Glasl L, Nussbaumer M, Palme R, Stein H, Wolferstätter M, Zeh R, Zimbelmann M, Holsboer F, Landgraf R (2008) Mice selected for high versus low stress reactivity: a new animal model for affective disorders. Psychoneuroendocrinology 33:839–862

    Article  PubMed  CAS  Google Scholar 

  • Touma C, Gassen NC, Herrmann L, Cheung-Flynn J, Bull DR, Ionescu IA, Heinzmann JM, Knapman A, Siebertz A, Depping AM, Hartmann J, Hausch F, Schmidt MV, Holsboer F, Ising M, Cox MB, Schmidt U, Rein T (2011) FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior. Biol Psychiatry 70:928–936

    Article  PubMed  CAS  Google Scholar 

  • Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, Bock R, Klein R, Schutz G (1999) Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 23:99–103

    Article  PubMed  CAS  Google Scholar 

  • Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397

    Article  PubMed  CAS  Google Scholar 

  • van den Brandt J, Luhder F, McPherson KG, de Graaf KL, Tischner D, Wiehr S, Herrmann T, Weissert R, Gold R, Reichardt HM (2007) Enhanced glucocorticoid receptor signaling in T cells impacts thymocyte apoptosis and adaptive immune responses. Am J Pathol 170:1041–1053

    Article  PubMed  Google Scholar 

  • van Gaalen MM, Stenzel-Poore MP, Holsboer F, Steckler T (2002) Effects of transgenic overproduction of CRH on anxiety-like behaviour. Eur J Neurosci 15:2007–2015

    Article  PubMed  Google Scholar 

  • Vicentini E, Arban R, Angelici O, Maraia G, Perico M, Mugnaini M, Ugolini A, Large C, Domenici E, Gerrard P, Bortner D, Mansuy IM, Mangiarini L, Merlo-Pich E (2009) Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice. Pharmacol Biochem Behav 93:17–24

    Article  PubMed  CAS  Google Scholar 

  • Wagner KV, Wang XD, Liebl C, Scharf SH, Muller MB, Schmidt MV (2011) Pituitary glucocorticoid receptor deletion reduces vulnerability to chronic stress. Psychoneuroendocrinology 36:579–587

    Article  PubMed  CAS  Google Scholar 

  • Warwick BP, Romsos DR (1988) Energy balance in adrenalectomized ob/ob mice: effects of dietary starch and glucose. Am J Physiol 255:R141–R148

    PubMed  CAS  Google Scholar 

  • Zhu Y, Pintar JE (1998) Expression of opioid receptors and ligands in pregnant mouse uterus and placenta. Biol Reprod 59:925–932

    Article  PubMed  CAS  Google Scholar 

  • Zorrilla EP, Tache Y, Koob GF (2003) Nibbling at CRF receptor control of feeding and gastrocolonic motility. Trends Pharmacol Sci 24:421–427

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Sabrina Bauer, Ursula Habersetzer and Cornelia Flachskamm for excellent technical assistance. Moreover, we thank Carola Hetzel for careful reading of the manuscript. This work was partially supported by the Bundesministerium für Bildung und Forschung within the framework of NGFN-Plus (Förderkennzeichen: 01GS08151 and 01GS08155) and by the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215).

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Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany

    Nina Dedic, Chadi Touma, Cristoph P. Romanowski, Marcel Schieven, Claudia Kühne, Martin Ableitner, Ailing Lu, Florian Holsboer, Mayumi Kimura & Jan M. Deussing

  2. Institute of Developmental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany

    Nina Dedic & Wolfgang Wurst

  3. Lehrstuhl für Entwicklungsgenetik, c/o Helmholtz Zentrum München, Technical University München-Weihenstephan, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany

    Wolfgang Wurst

  4. Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Standort München, Schillerstrasse 44, 80336, Munich, Germany

    Wolfgang Wurst

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  1. Nina Dedic
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  2. Chadi Touma
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  3. Cristoph P. Romanowski
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  4. Marcel Schieven
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  5. Claudia Kühne
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  6. Martin Ableitner
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  7. Ailing Lu
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  11. Jan M. Deussing
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Correspondence to Jan M. Deussing.

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Nina Dedic and Chadi Touma contributed equally to this work.

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Dedic, N., Touma, C., Romanowski, C.P. et al. Assessing Behavioural Effects of Chronic HPA Axis Activation Using Conditional CRH-Overexpressing Mice. Cell Mol Neurobiol 32, 815–828 (2012). https://doi.org/10.1007/s10571-011-9784-0

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