The Impact of Individual Vulnerability to Stress on Alcohol and Drug Seeking

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PROJECT SUMMARY Stress leads to the enhancement of memory in both humans and animals. This stress-enhanced memory has relevance to stress-related psychiatric disorders, such as posttraumatic stress disorder (PTSD), which is marked by heightened, perseverant memories of trauma. Interestingly, only approximately 10-20% of people develop the enduring symptoms of PTSD, despite nearly everyone experiencing at least one traumatic event in their lifetime. In addition, rates of PTSD are higher among women and military personnel. A protocol was developed by this group that results in differential susceptibility to stress enhancement of a remote (one month old) fear memory among male mice and a greater propensity for enhancement in females. Despite the clear importance of understanding the mechanisms supporting long-lasting, perseverant memory, the majority of basic memory research focuses on recent (~ 1 day old), not remote memory and does not incorporate a stress component. Additional research performed by the group with this protocol identified the basolateral amygdala (BLA) has a critical hub mediating stress-enhanced fear memory and the associated differential susceptibility. The primary goal of the current application is to delineate how stress engages and alters the function of the BLA to drive differential susceptibility to stress-enhanced fear memory. The work will place particular focus on sex as a biological variable and lateralized function of the BLA. Regarding the latter, the right hemisphere BLA is associated with negative valence, while the left is associated with positive valence. This is conserved from humans to rodents but is understudied in basic research. The central hypothesis of this proposal is that stress leads to lasting impacts on the BLA, resulting in differential susceptibility to remote stress-enhanced fear memory. The working hypothesis to be explored is that an intense acute stressor alters subsequent fear memory strength by influencing the recruitment of specific BLA cell populations to the memory trace. Work leading up to this proposal (F99 Aim 1A) details studies characterizing identity and laterality of neural ensembles supporting stress-induced memory enhancement. To examine how stress impacts experience coding to influence stress- enhanced fear memory (F99 Aim 1B), I will train in execution and data analysis of in vivo calcium imaging of the BLA. In transitioning to a postdoctoral fellowship, I will focus on research based on the high rate of co-morbidity between stress disorders and alcohol and substance sue disorders (K00). The research will incorporate neurophysiological and deep sequencing measures to further study how stress individually impacts function of the BLA and associated circuitry to influence alcohol or drug seeking. The proposed work will provide a much- needed, deep characterization of the impact of stress on the brain in the context of differential stress susceptibility. This information will then be used to guide cellular, molecular and circuit level mechanistic studies, with the goal of identifying therapeutic strategies.