PROJECT SUMMARY The goal of this project is to provide the building blocks for an independent research program focused on the neural basis of reward-based memory across distributed brain networks. Humans and other animals experience events in the moments they occur while the brain has evolved powerful neural processes to re-activate the neurons encoding these events in the ‘time in-between’. Reactivation of task-relevant neuronal ensembles occur during both wake and sleep states, and enable the binding and compression of neuronal representations in a temporal window compatible with neuronal plasticity. The role of awake and sleep reactivations in supporting episodic, hippocampus-dependent memories is well established. However, reactivation have been reported to also occur beyond the hippocampus, in both cortical and subcortical structures, and in both hippocampal- dependent and -independent tasks. This leads to the exciting possibility that reactivations may be a fundamental mechanism underlying memory formation and consolidation, and that they occur brain-wide, distributed among regions encoding different modalities and variables. However, their role in cue-driven, goal-directed sensorimotor tasks remain largely unexplored and evidence of multiregional reactivations is weak, in part because of technical difficulty to investigate neuronal population activity across multiple simultaneously recorded brain circuits. This proposal aims at testing the role of multi-region neuronal reactivations during wake and sleep in forming and consolidating associative networks to support reward-based learning. In the K99 phase, Dr. Drieu will focus on the role of multi-regional reactivation in cue-guided, goal-directed learning. She will test the hypothesis that the simultaneous reactivation of stimulus-, action-, and reward-selective neurons across brain regions during the waking state forms associative networks (Aim 1) subsequently reactivated during sleep for consolidation (Aim 2). In the R00 phase, Dr. Drieu will address whether transient synchronous activity spanning multiple brain areas in different brain states participate in the transition from cue-driven, allocentric memories to egocentric memories (Aim 3). To achieve these goals, Dr. Drieu will perform high-density, multi-site neuronal recordings using Neuropixels 2.0 combined with advanced closed-loop optogenetic methods in freely moving rats. The technical and scientific skills that Dr. Drieu will develop during the training period of this project will not only be crucial for the accomplishment of her immediate scientific goals, they will also become the pillars for the research she will develop in her own independent laboratory in the field of reward-based learning and memory. This training will be complemented by intense career developmental activities and mentorship that will prepare her for the practical aspects of laboratory management, teaching and fund raising. Overall, Dr. Drieu’s future research will provide new insights into the neural mechanisms involved in memory formation. This will lay the groundwork to better understand whether and how these mechanisms go awry in pathologies associated with reward-related disorders such as addiction, and with memory deficits such as Alzheimer’s disease.

PROJECT NARRATIVE The goal of this project is to address the crucial question of how reward-based memories are encoded in the brain. It will directly test the role of spontaneous reactivation of memory-relevant neurons distributed in multiple brain regions in memory formation and consolidation. These findings will be important not only for understanding the physiological basis of reward-based memories, but also relevant to human brain disorders such as addiction and Alzheimer’s disease.