Hippocampal-cortical mechanisms of altered memory consolidation in epilepsy

PROJECT SUMMARY/ABSTRACT This application presents a five-year mentored research and training plan that will prepare Dr. Sharon Chiang to be a leader in the field of hippocampal-cortical neuronal microcircuits in memory in epilepsy. Dr. Chiang completed her MD at Baylor College of Medicine and her PhD in Statistics at Rice University, where she was trained as a Bayesian statistician in the lab of Dr. Marina Vannucci, and is now a Clinical Fellow in Neurology at the University of California, San Francisco, in the Division of Epilepsy. Dr. Chiang's long-term career goal is to advance our understanding of the cellular circuits underlying memory in epilepsy and to investigate targeted manipulations to improve memory. This project will lay the basis of foundational studies for her independent research program focused on these aspects. Temporal lobe epilepsy (TLE) is the most common epilepsy in adults and affects more than 50 million people worldwide. There are no effective treatments for memory dysfunction in TLE, which stems from a lack of understanding of the fundamental mechanisms underlying memory impairment. Initially after an experience, the hippocampus repeatedly “replays” the memory at compressed timescales and transfers the memory to long-term storage in the neocortex. This replay of memories and the formation of a stable, long-term representation of the memory in the neocortex are critical to intact memory formation. Whether these critical elements are abnormal in TLE, and may be potential targets for manipulation, is unknown. This proposal leverages high-density, in vivo single neuron recordings in the hippocampus and neocortex in an experimental rat model of TLE, combined with real-time neurofeedback and electrical stimulation, to test the hypothesis that memory replay and formation of cortical memory-supporting neuronal ensembles are abnormal in TLE and that manipulations targeting these steps will improve memory. This work will generate fundamental knowledge about the role of two key neural circuitry steps in memory in TLE and may open avenues to new classes of targeted therapeutic manipulations. The proposed career development plan includes training in high-density flexible polymer probes, real-time neurofeedback, and electrical stimulation. Dr. Chiang will learn all of the skills needed for an independent research career, including mentoring/supervising trainees/staff, grant-writing, and scientific communication. She has assembled a world-class mentorship team with complementary expertise in hippocampal physiology, sharp- wave ripples, and memory (Primary mentor, Dr. Loren Frank); inhibitory microcircuits and closed-loop interventions in epilepsy (Scientific Advisor, Dr. Ivan Soltesz); rodent models of epilepsy and high-frequency oscillations (Scientific Advisor, Dr. Laura Ewell); electrical stimulation (Dr. Vikram R. Rao); neuroethics and rodent/human translation (Scientific Advisor, Dr. Daniel H. Lowenstein); and histopathology (Scientific Advisor, Dr. Cathryn Cadwell). Dr. Chiang, her mentors, and the Department of Neurology at UCSF are fully committed to this proposal and her development into an independent physician-scientist by the end of this training period.