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Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety

Nature Genetics volume 23, pages 99–103 (1999)Cite this article

Abstract

The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors1,2. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune and nervous system responses and ensure an adequate profile of transcription. In the brain, Gr has been proposed to modulate emotional behaviour, cognitive functions and addictive states3,4,5. Previously, these aspects were not studied in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth6 (F.T., C.K. and G.S., unpublished data). Therefore, we generated tissue-specific mutations of this gene using the Cre/loxP -recombination system7. This allowed us to generate viable adult mice with loss of Gr function in selected tissues. Loss of Gr function in the nervous system impairs hypothalamus-pituitary-adrenal (HPA)–axis regulation, resulting in increased glucocorticoid (GC) levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.

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Figure 1: Generation of mice deficient for Gr in the nervous system.
Figure 2: Mice lacking Gr in the nervous system display symptoms characteristic of Cushing syndrome including reduced size, altered fat distribution and reduced bone density.
Figure 3: Circulating corticosterone and Acth levels of control and GrNesCre mice.
Figure 4: HPA-axis activity in control and mutant mice.
Figure 5: Reduced anxiety-related behaviour in mutant animals.

References

  1. Tronche, F., Kellendonk, C., Reichardt, H.M. & Schütz, G. Genetic dissection of glucocorticoid receptor function in mice. Curr. Opin. Genet. Dev. 8, 532–538 (1998).

    Article  CAS  Google Scholar 

  2. Reichardt, H.M. et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531– 541 (1998).

    Article  CAS  Google Scholar 

  3. McEwen, B.S. & Sapolsky, R.M. Stress and cognitive function. Curr. Opin. Neurobiol. 5, 205– 216 (1995).

    Article  CAS  Google Scholar 

  4. De Kloet, E.R., Vreugdenhil, E., Oitzl, M.S. & Joels, M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301 ( 1998).

    CAS  PubMed  Google Scholar 

  5. Piazza, P.V. & Le Moal, M. Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annu. Rev. Pharmacol. Toxicol. 36, 359–378 (1996).

    Article  CAS  Google Scholar 

  6. Cole, T.J. et al. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 9, 1608–1621 (1995).

    Article  CAS  Google Scholar 

  7. Gu, H., Marth, J.D., Orban, P.C., Mossmann, H. & Rajewsky, K. Deletion of a DNA polymerase β gene segment in T cells using cell type-specific gene targeting. Science 265, 103–106 (1994).

    Article  CAS  Google Scholar 

  8. Zimmerman, L. et al. Independent regulatory elements in the nestin gene direct transgene expression to neural stem cells or muscle precursors. Neuron 12, 11–24 ( 1994).

    Article  CAS  Google Scholar 

  9. Miller, W.L. & Blake Tyrrel, J. in The Adrenal Cortex (eds Felig, P., Baxter, J.D. & Frohman, L.A.) 555– 711 (McGraw-Hill, New York, 1995).

    Google Scholar 

  10. Fink, G. in Mechanism of Negative and Positive Feedback of Steroids in the Hypothalamic-Pituitary System (eds Bittar, E.E. & Bittar, N.) 30– 100 (JAI-press, Greenwich, 1997).

    Google Scholar 

  11. Heym, C. Immunocytochemical correlates of an extrapituitary adrenocortical regulation in man. Histol. Histopathol. 12, 567– 581 (1997).

    CAS  PubMed  Google Scholar 

  12. Gagner, J.P. & Drouin, J. Tissue-specific regulation of pituitary proopiomelanocortin gene transcription by corticotropin-releasing hormone, 3′,5′-cyclic adenosine monophosphate, and glucocorticoids. Mol. Endocrinol. 1, 677–682 (1987).

    Article  CAS  Google Scholar 

  13. Shipston, M.J. Mechanism(s) of early glucocorticoid inhibition of adrenocorticotropin secretion from anterior pituitary corticotropes. Trends Endocrinol. Metab. 6, 261–266 ( 1995).

    Article  CAS  Google Scholar 

  14. Birnberg, N.C., Lissitzky, J.C., Hinman, M. & Herbert, E. Glucocorticoids regulate proopiomelanocortin gene expression in vivo at the levels of transcription and secretion. Proc. Natl Acad. Sci. USA 80, 6982–6986 ( 1983).

    Article  CAS  Google Scholar 

  15. van Haarst, A.D., Oitzl, M.S., Workel, J.O. & de Kloet, E.R. Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity. Endocrinology 137, 4935–4943 ( 1996).

    Article  CAS  Google Scholar 

  16. Gold, P.W. et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N. Engl. J. Med. 314, 1329– 1335 (1986).

    Article  CAS  Google Scholar 

  17. Holsboer, F. & Barden, N. Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr. Rev. 17, 187– 205 (1996).

    Article  CAS  Google Scholar 

  18. Korte, S.M., De Kloet, E.R., Buwalda, B., Bouman, S.D. & Bohus, B. Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test. Eur. J. Pharmacol. 301, 19–25 (1996).

    Article  CAS  Google Scholar 

  19. Jefferys, D. & Funder, J.W. Glucocorticoids, adrenal medullary opioids, and the retention of a behavioral response after stress. Endocrinology 121, 1006–1009 (1987).

    Article  CAS  Google Scholar 

  20. Shepherd, J.K., Grewal, S.S., Fletcher, A., Bill, D.J. & Dourish, C.T. Behavioural and pharmacological characterisation of the elevated "zero-maze" as an animal model of anxiety. Psychopharmacology (Berl) 116, 56– 64 (1994).

    Article  CAS  Google Scholar 

  21. Andreatini, R. & Leite, J.R. The effect of corticosterone in rats submitted to the elevated plus-maze and to to pentylenetetrazol-induced convulsions. Prog. Neuropsychopharmacol. Biol. Psychiatry 18, 1333–1347 (1994).

    Article  CAS  Google Scholar 

  22. Britton, K.T., Lee, G., Dana, R., Risch, S.C. & Koob, G.F. Activating and 'anxiogenic' effects of corticotropin releasing factor are not inhibited by blockade of the pituitary-adrenal system with dexamethasone. Life Sci. 39, 1281– 1286 (1986).

    Article  CAS  Google Scholar 

  23. Korte, S.M., de Boer, S.F., de Kloet, E.R. & Bohus, B. Anxiolytic-like effects of selective mineralocorticoid and glucocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze. Psychoneuroendocrinology 20, 385–394 (1995).

    Article  CAS  Google Scholar 

  24. Smythe, J.W., Murphy, D., Timothy, C. & Costall, B. Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats. Pharmacol. Biochem. Behav. 56, 507– 513 (1997).

    Article  CAS  Google Scholar 

  25. Pepin, M.C., Pothier, F. & Barden, N. Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature 355, 725–728 (1992).

    Article  CAS  Google Scholar 

  26. Montkowski, A. et al. Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J. Neuroendocrinol. 7, 841–845 (1995).

    Article  CAS  Google Scholar 

  27. Stenzel Poore, M.P., Heinrichs, S.C., Rivest, S., Koob, G.F. & Vale, W.W. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 14, 2579–2584 (1994).

    Article  CAS  Google Scholar 

  28. Timpl, P. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nature Genet. 19, 162–166 ( 1998).

    Article  CAS  Google Scholar 

  29. Smith, G.W. et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102 (1998).

    Article  CAS  Google Scholar 

  30. Sapolsky, R.M. Why stress is bad for your brain. Science 273, 749–750 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Bahner for computer tomography measurements; G. Brix for NMR studies; J. Peters for technical help; A. Berns for β-galactosidase-Cre–dependant reporter mice; M. Friedel, H. Glaser, S. Bettermann, C. Zacher, D. Bock and S. Jochim for technical assistance; A. Plueck and the EMBL transgenic service for generation of NesCre mice; and A. Bauer, A. Henn, F. Holsboer, T. Lemberger, T. Mantamadiotis, W. Schmid and R. Sprengel for helpful comments. F.T., on leave from the CNRS, was a recipient of EMBO long-term and EEC fellowships. The Deutsche Forschungsgemeinschaft, the European Community and the Volkswagen-Stiftung supported this work.

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Author notes

  1. François Tronche and Christoph Kellendonk: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Biology of the Cell I, Deutsches Krebsforschungzentrum, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    François Tronche, Christoph Kellendonk, Peter Gass, Katrin Anlag & Günther Schütz

  2. Institute of Anatomy, Universität des Saarlandes, Homburg, Germany

    Oliver Kretz & Rudolf Bock

  3. EMBL, Heidelberg, Germany

    Paul C. Orban & Rüdiger Klein

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Correspondence to Günther Schütz.

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Tronche, F., Kellendonk, C., Kretz, O. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 23, 99–103 (1999). https://doi.org/10.1038/12703

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