Bidirectional rescue of extreme genetic predispositions to anxiety: impact of CRH receptor 1 as epigenetic plasticity gene in the amygdala

Transl Psychiatry. 2014 Feb 11;4(2):e359. doi: 10.1038/tp.2013.127.


The continuum of physiological anxiety up to psychopathology is not merely dependent on genes, but is orchestrated by the interplay of genetic predisposition, gene x environment and epigenetic interactions. Accordingly, inborn anxiety is considered a polygenic, multifactorial trait, likely to be shaped by environmentally driven plasticity at the genomic level. We here took advantage of the extreme genetic predisposition of the selectively bred high (HAB) and low anxiety (LAB) mouse model exhibiting high vs low anxiety-related behavior and tested whether and how beneficial (enriched environment) vs detrimental (chronic mild stress) environmental manipulations are capable of rescuing phenotypes from both ends of the anxiety continuum. We provide evidence that (i) even inborn and seemingly rigid behavioral and neuroendocrine phenotypes can bidirectionally be rescued by appropriate environmental stimuli, (ii) corticotropin-releasing hormone receptor 1 (Crhr1), critically involved in trait anxiety, shows bidirectional alterations in its expression in the basolateral amygdala (BLA) upon environmental stimulation, (iii) these alterations are linked to an increased methylation status of its promoter and, finally, (iv) binding of the transcription factor Yin Yang 1 (YY1) to the Crhr1 promoter contributes to its gene expression in a methylation-sensitive manner. Thus, Crhr1 in the BLA is critically involved as plasticity gene in the bidirectional epigenetic rescue of extremes in trait anxiety.

MeSH terms

  • Animals
  • Anxiety / genetics*
  • Basolateral Nuclear Complex / metabolism*
  • Environment
  • Epigenesis, Genetic
  • Gene Expression / genetics*
  • Gene-Environment Interaction*
  • Genetic Predisposition to Disease*
  • Mice
  • Mice, Inbred Strains
  • Receptors, Corticotropin-Releasing Hormone / genetics*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • YY1 Transcription Factor / metabolism


  • Receptors, Corticotropin-Releasing Hormone
  • YY1 Transcription Factor
  • Yy1 protein, mouse
  • CRF receptor type 1