title: Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala.
abstract: 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.
authors.affiliation: Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, GA, USA.|Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Self Defense Forces Yokosuka Hospital, Yokosuka City, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Sawamura
authors.affiliation: Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, GA, USA.|Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Torsten
authors.identifier: http://orcid.org/0000-0001-7045-9229
authors.initials: T
authors.lastname: Klengel
authors.affiliation: Institut de Neurociènces, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Armario
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovanovic
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Norrholm
authors.affiliation: Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, GA, USA.|Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Howard Hughes Medical Institute, Emory University, Atlanta, GA, USA.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Raül
authors.initials: R
authors.lastname: Andero
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D013995:Time; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003345:Corticosterone; D003907:Dexamethasone; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5