Behavioral, molecular and sex-specific mechanisms of indirectly learned fear memory

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Project Summary/Abstract The broad goal of this proposal is to understand how fear memories are formed and stored in the brain. Post- traumatic stress disorder (PTSD) affects nearly 5% of the world population, however, current treatments have limited efficacy in reversing the symptoms of this disorder. Furthermore, females are more likely than males to develop PTSD, though the mechanisms controlling this sex-dependent predisposition remain equivocal. While established rodent fear conditioning models have aided in the elucidating the neurobiological mechanisms supporting the formation of fear memories that underlie PTSD, these focus almost exclusively on the individual experiencing the traumatic event. However, some cases of PTSD and associated anxiety disorders can be acquired by witnessing a traumatic event happen to someone else in close proximity. Despite this, few studies have examined the neurobiology of indirectly acquired fear memories and whether they differ from those of memories for directly experienced traumatic events. Furthermore, whether there are sex differences in the behavioral and molecular mechanisms of indirectly fear memories has yet to be explored. In our preliminary studies using an indirect fear conditioning procedure in which an observer rat watches a demonstrator rat associate an auditory cue with a mild footshock, we found that both male and female rats could indirectly acquire fear memories. Genetic loss of Fmr1, which produces deficits in social behavior, resulted in an enhancement of indirect fear memories, suggesting that social cues may not be the primary factor driving empathetically acquired fear. Importantly, we found unique changes in protein degradation targets in the amygdala of demonstrator and observer rats, suggesting unique molecular signatures for directly vs indirectly acquired fear memories. The work in this proposal is designed to build off of these preliminary data and answer important questions about the behavioral, molecular and sex-specific mechanisms controlling the formation of indirectly acquired fear memories. Using genetic rat lines and specific manipulations to the training (learning) experience, Aim 1 will systematically test the behavioral mechanisms (social, visual, olfactory, auditory) by which indirect fear memories are acquired and how this varies by sex. Aim 2 will use whole genome transcriptomic and proteomic approaches and well-established pharmacological manipulations to determine if the formation of directly and indirectly acquired fear memories requires similar transcriptional, translational and protein degradation mechanisms and whether this varies by sex. Collectively, this study will answer important questions about the sex-specific mechanisms controlling the formation of memories for indirectly acquired fear associations, which will be critical for the development of proper therapeutic interventions for the treatment of PTSD that is acquired empathetically.