Behaviors are performed in a variety of contexts, such as in different environments or with different goals and rewards. Retrieving memories that are appropriately associated with each context is a fundamental brain function, whose disruption is common in memory-related disorders like Alzheimer's disease. Neural circuits responsible for memory processing include the hippocampus and the entorhinal cortex. During spatial navigation in particular, switching between distinct memories in different contexts is thought to be mediated by hippocampal remapping - a process by which hippocampal activity switches between distinct spatial representations. Remapping is difficult to control experimentally and is not well understood at the level of neural circuit mechanisms. To address this issue, I recently designed and implemented a novel virtual reality system for 2D navigation in rats. Virtual reality allows computer control of the animal's environment, and enables recording and manipulating brain areas during instantaneous switches between contexts that do not interrupt behavior. In this proposal, I aim to address fundamental unanswered questions about remapping. I will first develop behavioral paradigms in virtual reality that trigger hippocampal remapping (Aim 1, K99 phase). I will then characterize the role of entorhinal inputs into the hippocampus during remapping (Aim 2, K99 phase). During this stage, I will also learn and develop pharmacological, optogenetic, and electronic circuit tools that will allow me to silence specific inputs into the hippocampus or target them for recordings during remapping (Aim 2, R00 phase). Finally, I will use the fast temporal resolution offered by virtual reality, coupled with neural activity decoding approaches and optogenetics to understand the relationship between hippocampal remapping and behavioral output (Aim 3, R00 phase). Together, these studies will test existing models and provide new testable ideas about the neural mechanisms underlying memory retrieval and its use in the brain. My principal mentor, Dr. David Tank, is a pioneer in developing virtual reality techniques and using them for hippocampal neurophysiology. His lab in the strong, collaborative Princeton University environment is therefore an ideal place for me to pursue these research goals. My training plan provides a detailed strategy for acquiring necessary skills in the K99 phase from a team of co-mentors with extensive experience in the relevant techniques. Knowledge of these techniques, combined with frequent data presentations, attendance of seminars and professional courses, and close interactions with the Princeton neuroscience community, will provide me with the necessary skills for transitioning to independence. In the independent R00 phase, I will use these acquired skills to complete the proposed aims and establish a laboratory focused on the study of memory processing with innovative behavioral, neurophysiological, and computational techniques.
Retrieving appropriate memories in different contexts is a fundamental brain function that depends on the hippocampus and the entorhinal cortex. This proposal will investigate these brain areas in rats using a virtual reality system that allows reliably manipulating the animal's sensory environment. The purpose of this research is to understand the neural mechanisms underlying memory-guided behaviors, with the eventual goal of understanding how they fail in memory-related disorders like Alzheimer's dementia.