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

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in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth6 (F.T., C.K. and G.S., unpublished data).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.

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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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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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