Molecular Mechanisms of Reconsolidation Boundaries

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): A central challenge for mental health research is to develop clinically effective methods to therapeutically attenuate maladaptive emotions. Some promising future treatments are aimed at attenuating emotional memories, targeting the phenomenon that when memories are reactivated, they appear to enter a transiently destabilized state which is believed to require re-stabilization via a process referred to as reconsolidation. Targeting the reconsolidation process has been proposed to be a potential treatment for many psychopathologies, including PTSD. For PTSD, blocking the reconsolidation of traumatic memories might attenuate these traumatic memories, in turn reducing PTSD pathology. However preclinical studies suggest that all emotional memories are not susceptible to treatments that block the reconsolidation process. For example induction of reconsolidation updating of strong reactivated aversive memories is impaired, consequently making these memories resistant to reconsolidation blockade. Since PTSD patients suffer from strong pathological memories, these preclinical data suggest that targeting the reconsolidation process in patients may have limited efficacy unless methods/strategies are developed to overcome this critical barrier. We hypothesize that inhibition of reconsolidation updating is caused by a change in the synaptic N-methyl D-aspartate receptor subunit NR2A/NR2B ratio. Additionally we hypothesize that altering the NR2A/B ratio can also have profound consequences on initial learning - a mechanism to explain in part age related cognitive decline. This project will examine how changing the NR2A/NR2B ratio within amygdala neurons effects learning and reconsolidation updating. We will accomplish this by increasing NMDA receptor subunits NR2A, NR2B or mutant NR2s via viral mediated gene delivery to amygdala neurons either before Pavlovian fear conditioning for the experiments studying learning or after fear conditioning for the experiments focusing on reconsolidation updating. We hypothesize that a high ratio of NR2A/NR2B will inhibit memory formation and a low ratio of NR2A/NR2B will promote memory formation. Additionally we hypothesize that overexpressing NR2B will promote the induction of reconsolidation updating and the overexpression of NR2A will inhibit reconsolidation updating. This project will answer a significant question of neurobiology - What is the function/consequence of the NR2A/B switch on learning & memory? Additionally this project will be the first of its kind to determine a biologically and possibly clinically relevant molecular explanation to why certain memories are susceptible to treatments that target the reconsolidation process while other memories are not. PUBLIC HEALTH RELEVANCE: Dysregulation of the fear system is associated with many psychiatric disorders underscoring the need for developing better treatments for pathological fear. This project aims to identify the mechanisms that contribute to the maintenance of pathological fear and provide the basis of a strategy for attenuating maladaptive fear memories.