Project Summary The R00 phase of this project will be conducted at the University of California, Irvine in the Department of Neurobiology and Behavior, School of Biological Sciences. Sleep is crucial for memory consolidation and its benefit is most commonly thought to occur via the reactivation of memories, thereby strengthening the neural infrastructure supporting them. Theoretical accounts of sleep-related consolidation focus on the process by which memories are independently strengthened, but in natural settings individual memories never exist in a vacuum. Importantly, the context in which memories are embedded during encoding governs retrieval and decision making behavior. However, context’s role in consolidation has not been directly explored. The goal of the proposed project is to improve our fundamental understanding of memory processes by developing an empirically-based framework unifying models of context’s effect on memory and models of sleep-related consolidation (Aim 1). Additionally, the framework will be used to support translational interventions to alter memories during sleep. Aim 2 will attempt to reinstate a suppression context during sleep to effectively weaken memories. This effort will inform future work on alleviating memory-related symptoms in clinical populations suffering from post-traumatic stress disorder. This project will combine novel techniques to selectively bias memory reactivation; machine-learning algorithms to decipher memory-related content from neural data; and neuroscientific methods for monitoring brain connectivity and rhythms in different regions and timescales. For Aim 1, functional MRI pattern analysis techniques will be used to reveal whether contexts, individual memories or both are reactivated during natural, undisturbed sleep. For Aim 2, the main behavioral manipulation used will be targeted memory reactivation, the unobtrusive presentation of learning-related stimuli during sleep, thereby enhancing memory. In one experiment included in Aim 2, individual memories will be embedded in a previously unrelated context during sleep: a reactivated “suppression” context (cued by an odor) will be presented with auditory cues linked to individual memories, hypothetically weakening them during sleep. An additional experiment will use a similar technique to try and alleviate distressful intrusive memories following a trauma manipulation in healthy participants. Taken together, these experiments should pave the way towards a richer understanding of the extent of memory reactivation during sleep, and toward content-specific interventions to selectively manipulate sleep, thereby improving mental health and wellbeing.