Journal Article

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Norrholm, Seth D, Jovanovic, Tanja, Sawamura, Takehito, Ressler, Kerry J, Andero, Raül, Armario, Antonio, Klengel, Torsten

2016

Overview

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

• Publisher: Nature Publishing Group
• Subject: Amygdala - drug effects / Amygdala - metabolism / Animals / Auditory Perception - drug effects / Auditory Perception - physiology / Corticosterone - blood / Dexamethasone - pharmacology / Disease Models, Animal / DNA methylation / Dose-Response Relationship, Drug / Epigenesis, Genetic / Epigenetics / Extinction, Psychological - drug effects / Extinction, Psychological - physiology / Fear - drug effects / Fear - physiology / Feedback / Freezing Reaction, Cataleptic - drug effects / Freezing Reaction, Cataleptic - physiology / Hormones / Learning - drug effects / Learning - physiology / Male / Mental disorders / Mice, Inbred C57BL / Original / Post traumatic stress disorder / Proteins / Psychiatry / Psychotropic Drugs - pharmacology / Receptors, Glucocorticoid - metabolism / RNA, Messenger - metabolism / Stress, Psychological - drug therapy / Stress, Psychological - metabolism / Tacrolimus Binding Proteins - metabolism / Time