Prefrontal pathway-specific modulation of protein synthesis in emotional memories - Abstract Long-term memories are often formed when the event involves a threat and triggers survival behavior. Sensory cues present during the threat tend to elicit defensive behaviors when they occur in the future, indicating that a long-term association has formed between the cue and the threat. While it is known for decades that the transformation of associative memories from labile state to long-term form requires new protein synthesis in discrete brain regions, there is a knowledge gap in the understanding of specific neural pathways that are recruited during memory consolidation and the mechanisms that control the dynamics of protein synthesis in these pathways. This knowledge is important not only for gaining a deeper understanding of spatiotemporally resolved protein synthesis in memory processes but also for targeted therapeutic intervention in disorders of emotional memories such as post-traumatic stress disorder (PTSD). PTSD is characterized by over-consolidation of memory about the traumatic event, inability to discriminate innocuous stimuli from ones that predict danger, and maladaptive coping strategies. Using Pavlovian and instrumental threat conditioning paradigms in mice, this proposal aims to understand the neurobiological substrates for the modulation of emotional memories by threat intensity and volitional control – both of which are disrupted in PTSD. Two key modes for protein synthesis, namely the eukaryotic initiation factor 2 (eIF2) and eIF4E-dependent translation, are thought to be crucial for associative emotional memories. The proposed study will use bidirectional strategies to regulate these modes of translation in specific prefrontal pathways connecting with deep brain regions, including the basolateral amygdala and paraventricular thalamus. Furthermore, this work will survey learning-induced physiological changes in the brain at the level of cellular-resolution molecular signaling. Finally, the study plans to determine the changes in the translation landscape in specific prefrontal pathways during the consolidation of diverse emotional memories that result in cue-elicited freezing or avoidance. To achieve these goals, mouse models will be used in combination with viral-mediated gene transfer, chemogenetics, pharmacology, imaging, molecular profiling, and behavior. Findings from this study have the potential to transform the field of memory research by elucidating the molecular players that govern the consolidation of long-term memories in both healthy and diseased brain states.
