European Journal of Psychotraumatology (Sep 2012)
CRH receptor genetic variation in a developmental primate model relevant to the risk to develop anxiety and depression
Abstract
Background : Using a well-established non-human primate model of anxious temperament (AT) we characterized alterations in the neural circuit that underlie the dispositional risk to develop anxiety and depression. Genetic variation encoding the CRHR1 and CRHR2 receptors was determined to examine the extent to which putative functional variants in the expression of these receptors may contribute to the expression of the risk phenotype as well as its underlying neural substrate. In a subset of monkeys, we sampled tissue from the central nucleus of the amygdala (Ce) to quantitate mRNA expression patterns. Methods : In a large cohort of young rhesus monkeys (n>300), all part of a multigenerational family pedigree, we characterized AT with threat-related behavioral and cortisol measures and its underlying neural circuit with FDG-PET. In all animals, all exons from these genes were sequenced and SNPs with potential functional significance were tested for their relation to AT and brain metabolism in regions underlying AT. Rhesus Affymetrix microarrays were used to determine Ce gene expression patterns. Results : Regarding CRHR1, we found that SNPs affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and Ce. Data will also be presented regarding variation in CRHR2 in relation to AT, cortisol, and underlying brain function. Gene expression data from the Ce demonstrated alterations in diverse systems, including neuroplasticity. Conclusions : These data suggest that genetic variation in CRHR1 and CRHR2 affects the risk for anxiety and affective disorders by influencing the function of the neural circuit underlying AT, and that differences in gene expression or the protein sequence involving CRHR1 exon 6 may be important. Exon 6 is of particular interest because its expression in primates is very different than that in non-primate species. In addition, Ce mRNA data implicate neuroplasticity systems in the development and maintenance of AT. These data suggest novel treatment approaches for early life interventions with the potential to decrease the risk of children with AT to develop anxiety and depressive disorders.
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