Mapping the brain pathways of traumatic memory: Inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats

Cohen, Hagit; Kozlovsky, Nitsan; Matar, Michael A.; Kaplan, Zeev; Zohar, Joseph

doi:10.1016/j.euroneuro.2009.12.006

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Volume 20, Issue 4 , Pages 253-271, April 2010

Mapping the brain pathways of traumatic memory: Inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats

Hagit Cohen
- Ministry of Health, Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
- Corresponding author. Anxiety and Stress Research Unit, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 4600, Beer-Sheva 84170, Israel. Tel.: +972 8 6401743; fax: +972 8 6401742.
Nitsan Kozlovsky
- Ministry of Health, Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Michael A. Matar
- Ministry of Health, Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Zeev Kaplan
- Ministry of Health, Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Joseph Zohar
- The Chaim Sheba Medical Center, Sackler Medical School, Tel-Aviv University, Tel Hashomer, Israel

Received 9 October 2009; received in revised form 15 November 2009; accepted 24 December 2009. published online 03 February 2010.

Abstract

Background

Protein kinase M zeta (PKMζ), a constitutively active isoform of protein kinase C, has been implicated in protein synthesis-dependent maintenance of long-term potentiation and memory storage in the brain. Recent studies reported that local application of ZIP, a membrane-permeant PKMζ inhibitor, into the insular cortex (IC) of behaving rats abolished long-term memory of taste associations.

Method

This study assessed the long-term effects of local applications of ZIP microinjected immediately (1h) or 10days after predator scent stress exposure, in a controlled prospectively designed animal model for PTSD. Four brain structures known to be involved in memory processes and in anxiety were investigated: lateral ventricle (LV), dorsal hippocampus (DH), basolateral amygdala and IC. The outcome measures included behavior in an elevated plus maze and acoustic startle response 7days after microinjection, and freezing behavior upon exposure to trauma-related cue 8days after microinjection. Previously acquired/encoded memories associated with the IC were also assessed.

Results

Inactivation of PKMζ in the LV or DH within 1h of exposure effectively reduced PTSD-like behavioral disruption and trauma cue response 8days later. Inactivation of PKMζ 10days after exposure had equivalent effects only when administered in the IC. The effect was demonstrated to be specific for trauma memories, whereas previously acquired data were unaffected by the procedure.

Conclusion

Predator scent related memories are located in different brain areas at different times beginning with an initial hippocampus-dependent consolidation process, and are eventually stored in the IC. These bring the IC to the forefront as a potential region of significance in processes related to traumatic stress-induced disorders.

Keywords: Post-traumatic stress disorder, Animal model, Protein kinase M zeta, Memory consolidation, Extreme behavioral response, Minimal behavioral response