Michelle A. Frazer - US grants

PROJECT SUMMARY The link between sleep and memory is well-established, though the underlying mechanisms involved are not fully understood. Disordered sleep has numerous negative consequences to health and cognition, and is itself often a symptom of psychiatric and neurological illnesses. A more complete understanding of the role of sleep in memory processing will further our knowledge of the mechanisms of learning and memory, as well as point to potential areas for intervention to improve cognitive function in disease states. The overarching goal of this project is to increase our understanding of rapid eye movement (REM) sleep and its role in sleep-dependent consolidation through delineating the necessity and function of oriens-lacunosum moleculare (OLM) interneurons in the hippocampus during this sleep state. Our preliminary data suggest that inhibiting all somatostatin-expressing neurons in the dorsal hippocampus during REM sleep results in deficits in memory consolidation in novel object placement recognition (NOPR) and contextual fear conditioning (CFC) tasks. Our hypothesis is that OLM interneuron activity is crucial for maintaining the balance of information flow into the CA1 region of the hippocampus, and that changing the activity of these cells during REM sleep will result in deficits in contextual memory consolidation. The work outlined in this proposal will build upon our preliminary data through the use of a novel mouse line selectively targeting OLM interneurons. In Aim 1, we will investigate the behavioral effects of both stimulating and inhibiting OLM cells during REM sleep following the acquisition of a hippocampal-dependent memory task. We will analyze the effect of OLM modulation during REM sleep on both NOPR and CFC tasks and use recorded LFP activity to study sleep architecture and oscillatory activity. Aim 2 will determine the effect of modulating OLM cell activity during REM sleep on the formation and maintenance of place cells. We will use optogenetics in combination with in vivo calcium imaging to identify place cells and observe how OLM cell modulation impacts place cell characteristics such as field size, firing rate, stability, and coherence. Completion of these aims will provide more information regarding the necessity of REM sleep for memory consolidation, and define the role of OLM cells in local hippocampal circuits during spatial memory processing. Experiments will take place in the lab of Dr. Gina Poe, an expert in the sleep and memory field. The Poe lab's expertise in hippocampal electrophysiology and rodent sleep, together with UCLA's strong interest in developing neurotechnology, places me in a strong position to use innovative approaches to investigate these questions. The training plan described below will emphasize building strong data analysis skills through courses and workshops in statistics and programming, a solid foundation in cutting- edge systems neuroscience techniques through experiments and courses proposed, and grant-writing and scientific communication abilities through opportunities to present and publish my results in a variety of venues.