PROJECT SUMMARY Dysfunction in the stability of long-term memories is a core symptom of many neuropsychiatric disorders, including Alzheimer’s disease, major depression, and post-traumatic stress disorder. The process by which newly formed memories are stabilized into more permanent storage is known as memory consolidation. The hippocampus (HPC) has a well-established role in the initial formation and storage of memory. Over the course of days-to-months, memory recall is thought to become increasingly dependent on cortical regions, such as the anterior cingulate cortex (ACC). How memory is reorganized at the systems level between HPC and ACC remains poorly understood. Recent studies implicate an intermediate brain region, the entorhinal cortex (EC), as facilitating consolidation of memories. Disrupting the EC impairs the ability of new memories to be stored over long durations. However, it remains unclear when and how EC may contribute to memory consolidation. We hypothesize that EC is recruited at the time of learning to stabilize neurons and neural ensembles in ACC that represent a learned association. This project will test this by utilizing methods of monitoring and manipulating the dynamics of brain-wide circuits over extended periods of time through three specific aims. In aim one, we will first develop a novel virtual-reality based contextual learning task in head-fixed mice, allowing us to probe the learning and recall of memories throughout the duration of consolidation (weeks-to-months). The EC-ACC projection will be selectively inhibited at various time points to quantify its role in remote memory recall. In aim 2, we will record bulk neural activity from HPC, EC, and ACC using chronically implanted optical fibers (fiber photometry) to track interregional interactions and the emergence of neural correlates of memory during memory consolidation. In aim 3, we will perform two photon calcium imaging in ACC throughout memory retrieval including recent and remote time points. The EC-ACC projection will be selectively inhibited and the effect of this circuit on neural representations of memory at remote time points will be quantified. This investigation will fill a substantial gap in our understanding of systems consolidation and facilitate new insights into the distributed dynamics of memory in psychiatric health and disease. The applicant’s career goal is to be an academic physician-scientist with a research program aimed at bridging the gap between basic systems neuroscience research and clinical treatments. He is pursuing MD-PhD training at Weill Cornell Medical College and The Rockefeller University, and will develop research, scientific communication, and clinical expertise skills during this fellowship.