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CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression

Molecular Psychiatry volume 18, pages 700–707 (2013)Cite this article

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Abstract

The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with 18F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.

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Acknowledgements

This work has been supported by National Institutes of Health Grants MH046729 (to NHK), MH081884 (to NHK and JR), MH084051 (to RJD and NHK), the HealthEmotions Research Institute and the Baylor College of Medicine. We thank the staff at the Wisconsin National Primate Center, the Harlow Center for Biological Psychology, the Waisman Laboratory for Brain Imaging and Behavior, P. Roseboom, H. Van Valkenberg, K. Myer, E. Larson, M. Riedel and J. Storey. We also thank Matthew Bainbridge (BCM) for annotation software and Panagiotis Katsonis (BCM) for assistance with comparative protein alignments. We would like to acknowledge the seminal contributions of Wylie Vale in relation to CRF biology and dedicate this manuscript in fond memory of his friendship, collegiality and support.

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Authors and Affiliations

  1. Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    J Rogers, M Raveendran, G L Fawcett, D M Muzny & R A Gibbs

  2. Southwest National Primate Research Center, San Antonio, TX, USA

    J Rogers

  3. Department of Psychology, University of Wisconsin, Madison, WI, USA

    A S Fox, R J Davidson & N H Kalin

  4. Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA

    A S Fox, R J Davidson & N H Kalin

  5. Department of Psychiatry, University of Wisconsin, Madison, WI, USA

    S E Shelton, J A Oler, R J Davidson & N H Kalin

  6. HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA

    S E Shelton, J A Oler, R J Davidson & N H Kalin

  7. Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA

    J Cheverud

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Correspondence to J Rogers.

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Competing interests

NHK is the founder and principal owner of a company, Promoter Neuroscience, which is focused on developing tools and finding drugs that affect expression of genes in the CRH family. He also holds the following patents:

Promoter sequences for corticotropin-releasing factor CRF2alpha and method of identifying agents that alter the activity of the promoter sequences: US Patent issued on 07-04-06; patent No. 7,071,323 and US Patent issued on 05-12-09; patent No. 7,531,356;

Promoter sequences for urocortin II and the use thereof: US Patent issued on 08-08-06; patent No. 7,087,385; and

Promoter sequences for corticotropin-releasing factor binding protein and use thereof: US Patent issued on 10-17-06; patent No. 7,122,650.

The other authors declare no conflicts of interest.

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Rogers, J., Raveendran, M., Fawcett, G. et al. CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression. Mol Psychiatry 18, 700–707 (2013). https://doi.org/10.1038/mp.2012.152

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