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

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 (1 h) or 10 days 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 7 days after microinjection, and freezing behavior upon exposure to trauma-related cue 8 days after microinjection. Previously acquired/encoded memories associated with the IC were also assessed. Results: Inactivation of PKMζ in the LV or DH within 1 h of exposure effectively reduced PTSD-like behavioral disruption and trauma cue response 8 days later. Inactivation of PKMζ 10 days 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.