Stress‐induced Neuroadaptations in the Paraventricular Hypothalamic Nucleus of Animals that Exhibit Persistent Avoidance

Abstract

Individuals with PTSD exhibit increases in avoidance of trauma-related stimuli and blunted hypothalamo-pituitary adrenal (HPA) axis activation. Our laboratory has established a rodent model of traumatic stress that mimics the avoidance symptoms of PTSD. Animals are classified as ‘Avoiders' or ‘Non-Avoiders' based on avoidance of predator-odor paired context. We previously demonstrated that Avoiders exhibit an attenuated HPA response to predator odor. Glucocorticoids are the primary mediator of HPA negative feedback to the brain. Glucocorticoid receptor (GR) activation requires various accessory proteins that allow for translocation into the nucleus and transcriptional regulation of target genes. The FKBP5 gene, encoding binding protein FKBP51, is an important co-chaperone of the GR complex involved in regulating HPA negative feedback. FKBP51 prevents GR translocation to the nucleus, thus low FKBP5 results in enhanced negative feedback. We hypothesize that attenuated FKBP5 gene expression contributes to the hypofunctional HPA stress response in Avoiders. In this study, 50% of rats were classified as Avoiders. No differences in gene expression of the GR co-chaperones, Ncor1, FKBP5 and FKBP4 were noted in the paraventricular nucleus (PVN) of Non-Avoiders and Avoiders. There was a significant increase in NR3C1 (GR) gene expression in the PVN of Non-Avoiders compared to controls. These results suggest that stress-induced neuroadaptions in the GR complex may contribute to HPA dysfunction in Avoiders. The potential contribution of HPA dysfunction to stress-induced behaviors is the focus of current studies. This work was supported by NIH grants: AA018400 (NWG), AA023305 (NWG), and LSUHSC pilot grant (AMW).