ИСТИНА

The mechanisms of post-traumatic stress disorder (PTSD) have attracted increasing attention in recent years. However, despite the great success in the study of PTSD at the behavioral, psychological and physiological level in humans, as well as large number animal models of PTSD, the phenomenon of PTSD remains largely incomprehensible in theoretical terms. The aim of this project is to establish the neural basis for the pathological stability of traumatic memory that formed when encountering a stressful situation leading to the development of PTSD and to study the differences between the mechanisms of normal and traumatic memory formation at the neural level. First, we subjected mice to single traumatic experience and studied the dependence of PTSD development on protein synthesis during the consolidation and reconsolidation of traumatic memory. Mice injected with protein synthesis inhibitor cycloheximide (90 mg/kg, i.p.) 30 min before PTSD induction retained contextual associative memory but did not show a pronounced contextual fear. The results of elevated plus maze test suggests that the protein synthesis inhibition during the consolidation of traumatic memory can not only prevent the development of PTSD, but also disrupt the natural defensive behavior of animals, making them less anxious than control mice who had no previous negative experience. Than we showed that protein synthesis inhibition during the reconsolidation of traumatic memory almost completely abolish non-specific symptoms of trauma in mice, such as increased sensitization, fear generalization and anxiety. At the same time, however, cycloheximide injection during reminder did not affect the associative fear memory. These results show a dissociation between associative and nonassociative consequences of a traumatic experience in terms of their sensitivity to impairment during memory retrieval. We also studied the dependence of PTSD development on de novo methylation processes. Methyltransferase inhibitors 5-AZA and RG108 injection (0.5 mg/kg, i.p.) 30 min before traumatic episode reduced PTSD symptoms in mice: it decreased the level of conditioned fear and affected the level of behavioral sensitization and anxiety, but not the generalization. The inhibition of methylation processes during the reconsolidation of traumatic memory did not affect the symptoms of PTSD according to our data. We analyzed the c-Fos activity of the brain in the formation of normal contextual fear memory (FC) and traumatic memory in order to answer the second question of this project. The formation of traumatic memory was accompanied by activation of a pattern of brain areas similar to that activated during formation of FC memory. However, in PTSD the activity of amygdala, prelimbic cortex and dentate gyrus was considerably more pronounced. These results show important differences between normal and traumatic forms of memory at the time of their formation. In addition we hypothesize that increased activation of the amygdala and prefrontal cortex in PTSD may be associated with pathological persistence of traumatic memory.