Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I.

ABSTRACT

Two animal models of trait anxiety, HAB/LAB rats and mice, are described, representing inborn extremes in anxiety-related behavior. The comprehensive phenotypical characterization included basal behavioral features, stress-coping strategies and neuroendocrine responses upon stressor exposure with HAB animals being hyper-anxious, preferring passive coping, emitting more stressor-induced ultrasonic vocalization calls and showing typical peculiarities of the hypothalamic-pituitary-adrenocortical axis and line-specific patterns of Fos expression in the brain indicative of differential neuronal activation. In most cases, unselected Wistar rats and CD1 mice, respectively, displayed intermediate behaviors. In both HAB/LAB rats and mice, the behavioral phenotype has been found to be significantly correlated with the expression of the neuropeptide arginine vasopressin (AVP) at the level of the hypothalamic paraventricular nucleus (PVN). Additional receptor antagonist approaches in HABs confirmed that intra-PVN release of AVP is likely to contribute to hyper-anxiety and depression-like behavior. As shown exemplarily in HAB rats and LAB mice, single nucleotide polymorphisms (SNPs) in regulatory structures of the AVP gene underlie AVP-mediated phenotypic phenomena; in HAB rats, a SNP in the promoter of the AVP gene leads to reduced binding of the transcriptional repressor CBF-A, thus causing AVP overexpression and overrelease. Conversely, in LAB mice, a SNP in the AVP gene seems to cause an amino acid exchange in the signal peptide, presumably leading to a deficit in bioavailable AVP likely to underlie the total hypo-anxiety of LAB mice in combination with signs of central diabetes insipidus. Another feature of LAB mice is overexpression of glyoxalase-I. The functional characterization of this enzyme will determine its involvement in anxiety-related behavior beyond that of a reliable biomarker. The further identification of quantitative trait loci, candidate genes (and their products) and SNPs will not only help to explain inter-individual variation in emotional behavior, but will also reveal novel targets for anxiolytic and antidepressive interventions.