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Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2

Abstract

Corticotropin-releasing hormone1,2 (Crh), a 41-residue polypeptide, activates two G-protein–coupled receptors, Crhr1 (refs 35) and Crhr2 (refs 69), causing (among other transductional events) phosphorylation of the transcription factor Creb (ref. 10). The physiologic role of these receptors is only partially understood. Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1 (refs 11,12). The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2−/− mice. We propose that Crhr2 predominantly mediates a central anxiolytic response, opposing the general anxiogenic effect of Crh mediated by Crhr1. Neither male nor female Crhr2-deficient mice show alterations of baseline feeding behaviour. Both respond with increased edema formation in response to thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender.

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Figure 1: Generation of Crhr2−/− mice.
Figure 2: Anxious behaviour of Crhr2-deficient male mice.
Figure 3: Effects of Crhr1 stimulation and Crhr2 blockade on anxiety and locomotion.
Figure 4: Behaviour of female wild-type, Crhr2+/− and Crhr2−/− mice in the elevated plus maze test under baseline conditions (a) and 30 min after a 1 h immobilization stress (b).
Figure 5: Imunohistochemical detection of pCreb and c-Fos in male wild-type and Crhr2-null mutants 1 h after a 5-min exposure to the elevated plus-maze test.
Figure 6: Baseline and stress-induced levels of Acth and corticosterone in male (a) and female (b) wild-type, Crhr2+/− and Crhr2−/− mice (n=5 or 6 mice per sex per genotype).

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Acknowledgements

We thank M. Ayers, M. Fisher, C. Todorovic, K. Eckart, T. Liepold and A. Burgdorf for discussions and assistance. O.H. is supported by the Swedish Brain Foundation. M.G.R. is an investigator with the Howard Hughes Medical Institute. This work is supported by NIH grants to M.G.R. and MPG funds to J.S.

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Correspondence to Michael G. Rosenfeld or Joachim Spiess.

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Kishimoto, T., Radulovic, J., Radulovic, M. et al. Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat Genet 24, 415–419 (2000). https://doi.org/10.1038/74271

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