Final Report Summary - GENANX (A cross-species neurogenomics approach to anxiety)
Chronic psychosocial stress is a well-established risk factor for anxiety disorders, but the development of targets for therapeutic intervention is greatly limited by ignorance of the molecular and cellular mechanisms associated with susceptibility and resilience to these common conditions. To identify the gene-environment interactions that underline chronic psychosocial stress, we applied controlled environmental stress to mice from four different inbred backgrounds. We established that the behavioral and brain transcriptomic stress was highly dependent on the background, suggesting strong gene-environment interactions. We identified several biological pathways that were differentially expressed between stress resilient, stress susceptible and control mice. One of these pathways was related to myelin plasticity, and in follow-up experiments, we found significant differences in myelin thickness in anxiety-associated brain regions of the mice. Furthermore, we observed more white matter diffusivity in human subjects with subclinical anxiety, suggesting that white matter diffusivity may be a vulnerability factor for anxiety disorders. In addition to RNA-sequencing, we also carried out miRNA-sequencing from the same samples. We identified a number of miRNAs that where differentially expressed between stress susceptible and control, or stress resilient and control mice. We bioinformatically integrated these data with the RNA-sequencing data and found specific miRNA-mRNA-networks whose expression was affected by chronic stress. Overall, our comprehensive analysis, suggests that genetic background has a large effect on the transcriptomic to stress. Furthermore, we provide evidence of specific biological pathways being affected by chronic stress, including adult myelination, a newly discovered form of brain plasticity.