A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder |
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| Affiliation: | 1. Ministry of Health Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel;2. Division of Psychiatry, Chaim Sheba Medical Center, Sackler Medical School, Tel-Aviv University, Tel Hashomer, Israel;1. Department for Traumatology and Bone & Joint Surgery, Clinics for Surgery, Clinical Hospital Center Zagreb, Zagreb, Croatia;2. Department for Surgery, General Hospital Karlovac, Karlovac, Croatia;1. National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA;2. Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA;3. Department of Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA;4. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA;5. Pharmacogenomics Analysis Laboratory, Research Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA;6. Translational Research Center for TBI and Stress Disorders and Geriatric Research, Educational and Clinical Center, VA Boston Healthcare System, Boston, MA, USA;7. Department of Psychiatry, Harvard Medical School, Boston, MA, USA;1. Department of Anatomy and Neuroscience, University College Cork, Ireland;2. APC Microbiome Ireland, University College Cork, Ireland;1. Department of Pharmacology and Systems Physiology, University of Cincinnati, USA;2. Neuroscience Graduate Program, University of Cincinnati, USA;3. Neuroscience Undergraduate Program, University of Cincinnati, USA;4. Veterans Affairs Medical Center, Cincinnati, OH, USA |
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| Abstract: | BackgroundActivation of glucocorticoid receptors (GR) increases expression of the mitogen-activated protein kinase (MAPK) pathway leading to increased expression of Zif/268, an effector immediate early gene involved in cellular growth, intracellular signaling, and synaptic modification. Glucocorticoids induce expression of Zif/268 through two distinct mechanisms: a rapid-onset, MAPK-independent pathway and a slower-onset, MAPK-dependent mechanism.MethodThis study investigated both rapid and long-term expression of GR protein in the cytosolic extract, its translocation to the nucleus, and expression of mRNA for the Zif/268 gene in selected brain areas, associated with circulating levels of corticosterone, in an animal model of PTSD. Trauma cue-triggered Zif/268 expression was assessed eight days after stress exposure.ResultsThe results demonstrated a pattern of response that was common to all exposed individuals at 30 min after exposure, characterized by a significant elevation in GR translocation to the nucleus and elevated levels of Zif/268 mRNA in the hippocampus. A distinct pattern associated with extreme behavioral response (EBR) was revealed upon further bioassay of behavioral response groups, classified according to their individual patterns of behavioral response at seven days. These EBR individuals displayed significantly higher circulating corticosterone and nuclear GR levels, compared to minimal behavioral responders and controls. No difference in Zif/268 mRNA levels was observed between the exposed and naïve animals.ConclusionFollowing the uniform acute response, the patterns of GR protein levels and Zif/268 mRNA levels are associated with degree of behavioral disruption. Since the slower-onset mechanism for glucocorticoid-induced Zif/268 expression depends on activation of the MAPK pathway, the pattern observed only in EBR rats may be related to disruptions of this pathway. |
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