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.


METHODS
This 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.


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 naïve animals.


CONCLUSIONS
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.
Kozlovsky
Nitsan
N
Ministry of Health Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Matar
Michael A
MA
Kaplan
Zeev
Z
Zohar
Joseph
J
Cohen
Hagit
H
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism; D002415:Cats; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D018782:Maze Learning; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013216:Reflex, Startle / Q000502:physiology*; D013313:Stress Disorders, Post-Traumatic / Q000503:physiopathology; D013315:Stress, Psychological / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003345:Corticosterone