Original Article

Molecular Psychiatry (2017) 22, 733–744; doi:10.1038/mp.2016.136 published online 6 September 2016

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

R Zhang1,2,3, M Asai1,4, C E Mahoney5, M Joachim1, Y Shen1, G Gunner6 and J A Majzoub1

  1. 1Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
  2. 2Key laboratory of Resource Biology and Biotechnology in Western China; College of Life Science, Northwest University, Xi’an, Shaanxi, China
  3. 3Division for Experimental Natural Science, Faculty of Arts and Science, Kyushu University, Fukuoka, Japan
  4. 4Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  5. 5Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  6. 6Neurodevelopmental Behavior Core, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: R Zhang or Professor J Majzoub, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 300 longwood avenue, CLSB 16028, mailstop BCH3151, Boston, MA 02115, USA. E-mail: Rong.Zhang@childrens.harvard.edu or Joseph.Majzoub@childrens.harvard.edu

Received 29 February 2016; Revised 17 June 2016; Accepted 13 July 2016
Advance online publication 6 September 2016

Top

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.