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Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

Abstract

Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream. Acth in turn activates Acth receptors in the adrenal cortex to increase synthesis and release of glucocorticoids1. The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn), a Crh-related peptide, is thought to be the endogenous ligand for Crhr2 because it binds with almost 40-fold higher affinity than does Crh (ref. 2). Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues3,4,5,6. We generated mice deficient for Crhr2 to determine the physiological role of this receptor. Crhr2-mutant mice are hypersensitive to stress and display increased anxiety-like behaviour. Mutant mice have normal basal feeding and weight gain, but decreased food intake following food deprivation. Intravenous Ucn produces no effect on mean arterial pressure in the mutant mice.

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Figure 1: Generation of Crhr2-deficient mice.
Figure 2: Hypersensitivity of HPA axis to stress in mutant animals.
Figure 3: Effect of 24-h food deprivation on food intake in wild-type and mutant littermate mice.
Figure 4: Increased anxiety-like behaviour of mutant animals as measured in the elevated plus maze and open-field test.
Figure 5: Increased levels of Ucn and Crh mRNA in mutant brain
Figure 6: Cardiovascular responses to intravenous infusion of 1.0 μg Ucn in wild-type (n=5) and mutant (n=3; filled bars) mice.

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References

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

    Article  CAS  Google Scholar 

  2. Vaughan, J. et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378, 287–292 (1995).

    Article  CAS  Google Scholar 

  3. Perrin, M. et al. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc. Natl Acad. Sci. USA 92, 2969–2973 (1995).

    Article  CAS  Google Scholar 

  4. Lovenberg, T.W. et al. Cloning and characterization of a functionally distinct corticotropin- releasing factor receptor subtype from rat brain Proc. Natl Acad. Sci. USA 92, 836–840 (1995).

    Article  CAS  Google Scholar 

  5. Kishimoto, T., Pearse, R.V. 2nd, Lin, C.R. & Rosenfeld, M.G. A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle. Proc. Natl Acad. Sci. USA 92, 1108–1112 (1995).

    Article  CAS  Google Scholar 

  6. Stenzel, P. et al. Identification of a novel murine receptor for corticotropin-releasing hormone expressed in the heart. Mol. Endocrinol. 9, 637–645 (1995).

    CAS  PubMed  Google Scholar 

  7. 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 

  8. Spina, M. et al. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 273, 1561–1564 (1996).

    Article  CAS  Google Scholar 

  9. 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 

  10. Hogg, S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol. Biochem. Behav. 54, 21–30 (1996).

    Article  CAS  Google Scholar 

  11. Rodgers, R.J. Animal models of ‘anxiety’: where next? Behav. Pharmacol. 8, 477–496 (1997).

    Article  CAS  Google Scholar 

  12. Belzung, C. & Le Pape, G. Comparison of different behavioral test situations used in psychopharmacology for measurement of anxiety. Physiol. Behav. 56, 623–628 (1994).

    Article  CAS  Google Scholar 

  13. Coste, S.C. et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nature Genet. 24, 403–409 (2000).

    Article  CAS  Google Scholar 

  14. Moreau, J.L., Kilpatrick, G. & Jenck, F. Urocortin, a novel neuropeptide with anxiogenic-like properties. Neuroreport 8, 1697–1701 (1997).

    Article  CAS  Google Scholar 

  15. Chalmers, D.T., Lovenberg, T.W. & De Souza, E.B. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 15, 6340–6350 (1995).

    Article  CAS  Google Scholar 

  16. Liang, K.C. et al. Lesions of the central nucleus of the amygdala, but not the paraventricular nucleus of the hypothalamus, block the excitatory effects of corticotropin-releasing factor on the acoustic startle reflex. J. Neurosci. 12, 2313–2320 (1992).

    Article  CAS  Google Scholar 

  17. King, F.A. & Meyer, P.M. Effects of amygdaloid lesions upon septal hyperemotionality in the rat. Science 128, 655–656 (1958).

    Article  CAS  Google Scholar 

  18. Melia, K.R. & Davis, M. Effects of septal lesions on fear-potentiated startle, and on the anxiolytic effects of buspirone and diazepam. Physiol. Behav. 49, 603–611 (1991).

    Article  CAS  Google Scholar 

  19. Lee, Y. & Davis, M. Role of the septum in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. J. Neurosci. 17, 6424–6433 (1997).

    Article  CAS  Google Scholar 

  20. Allen, J.P. & Allen, C.F. Amygdalar participation in tonic Acth secretion in the rat. Neuroendocrinology 19, 115–125 (1975).

    Article  CAS  Google Scholar 

  21. Beaulieu, S., Di Paolo, T. & Barden, N. Control of ACTH secretion by the central nucleus of the amygdala: implication of the serotoninergic system and its relevance to the glucocorticoid delayed negative feedback mechanism. Neuroendocrinology 44, 247–254 (1986).

    Article  CAS  Google Scholar 

  22. Beaulieu, S., Di Paolo, T., Cote, J. & Barden, N. Participation of the central amygdaloid nucleus in the response of adrenocorticotropin secretion to immobilization stress: opposing roles of the noradrenergic and dopaminergic systems. Neuroendocrinology 45, 37–46 (1987).

    Article  CAS  Google Scholar 

  23. Marcilhac, A. & Siaud, P. Regulation of the adrenocorticotrophin response to stress by the central nucleus of the amygdala in rats depends upon the nature of the stressor. Exp. Physiol. 81, 1035–1038 (1996).

    Article  CAS  Google Scholar 

  24. Bale, T.L. & Dorsa, D.M. Sex differences in and effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the ventromedial hypothalamus. Endocrinology 136, 27–32 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Creehan for animal assistance; G. Naeve for help with the image analysis; R. Picetti for help with behavioural analysis; S. Fitzpatrick for editorial assistance; and M. Stenzel-Poore and colleagues for sharing unpublished results. This work was supported in part by grants from the NIH (DK-26741), the Robert J. and Helen C. Kleberg Foundation, the Ludwick Family Foundation and The Foundation for Research. T.L.B. and G.W.S. were supported by NRSA fellowships DK09841 and DK09551, respectively. K.L.F. is a Pew Scholar.

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Correspondence to Kuo-Fen Lee.

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Bale, T., Contarino, A., Smith, G. et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 24, 410–414 (2000). https://doi.org/10.1038/74263

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