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Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

Molecular Psychiatry volume 22, pages 733–744 (2017)Cite this article

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Abstract

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light–dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

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Acknowledgements

We thank Drs Clifford B Saper and Nick Andrews for their helpful discussion. We acknowledge the BCH Neurodevelopmental Behavior Core (IDDRC, P30 HD 18655) and the Rodent Histopathology Core labaratory, Harvard Medical School for their technical support. We thank Dr Bradford Lowell for the kind gift of Crh-ires-Cre mice. This study was supported by National Institutes of Health Grants 5K01MH096148-03 (to RZ), T32DK007699-30 (to JAM) and NNSFC 31271095 (to RZ).

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Authors and Affiliations

  1. Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    R Zhang, M Asai, M Joachim, Y Shen & J A Majzoub

  2. Key laboratory of Resource Biology and Biotechnology in Western China;,

    R Zhang

  3. College of Life Science, Northwest University, Xi’an, Shaanxi, China

    R Zhang

  4. Division for Experimental Natural Science, Faculty of Arts and Science, Kyushu University, Fukuoka, Japan

    R Zhang

  5. Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M Asai

  6. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    C E Mahoney

  7. Neurodevelopmental Behavior Core, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    G Gunner

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Zhang, R., Asai, M., Mahoney, C. et al. Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice. Mol Psychiatry 22, 733–744 (2017). https://doi.org/10.1038/mp.2016.136

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