DESCRIPTION (provided by applicant): It is well established that new episodic and contextual memories are stored in the hippocampus. Over time, these memories are transferred to the cortex through a process called systems consolidation. This process is assumed to occur during periods of inactivity and sleep when the hippocampus replays newly acquired information. Replay is thought to drive the formation of intra-cortical connections that eventually allow memory to be retrieved without input from the hippocampus. Although these assumptions are widely accepted in the field, there is little direct evidence to support them. To address this significant gap in our knowledge, we will use recently developed genetic tools to: 1) identify and control hippocampal neurons that are active during learning and 2) determine if reactivation of these cells is necessary and sufficient for memory retrieval and long-term storage in the cortex. We will accomplish these goals by using newly generated transgenic mice to permanently label neurons that are active during learning. Tagging these cells will allow us to identify networks in the hippocampus and cortex that encode memory and follow their activity during the consolidation period. Next, we will use optogenetic and pharmacogenetic tools to control the activity of labeled hippocampal neurons and determine the effects on long-term memory storage in the cortex. Standard models of consolidation predict that hippocampal stimulation will reactivate cortical neurons that were tagged during learning and induce long-term storage. In contrast, silencing hippocampal ensembles after learning should prevent consolidation and induce amnesia. Our experiments will either: a) substantiate these long-held assumptions and provide mechanistic insight or b) refute these assumptions and provide a new framework for understanding the contributions of the hippocampus to memory consolidation.

PUBLIC HEALTH RELEVANCE: A number of human disorders affect the hippocampus and long-term memory (depression, schizophrenia, dementia, stroke, PTSD). Consequently, a major goal in neuroscience is to understand the mechanisms by which this structure stores and retrieves information. The current project will use an innovative set of genetic tools to determine how interactions between the hippocampus and cortex facilitate the formation of long-term memories. These tools can also be applied to mouse models of human disorders to determine how altered brain interactions lead to deficits in memory.