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

Background: Activation 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. Method: This study investigated both rapid and tong-term expression of GR protein in the cytosotic 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. Results: The 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 naive animals. Conclusion: Following 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. (C) 2009 Elsevier B.V. and ECNP. All. rights reserved.