WHAT IS LONG-TERM MEMORY? INVESTIGATING THE NEURONAL STRUCTURES AND MOLECULAR MECHANISMS OF MEMORY STORAGE IN ENGRAM CELLS

Memory is the capacity of an organism to acquire, store and recover information based on experience. In the brain, experiences that become memories appear as enduring changes only in a small set of activated neurons, called engrams. While the mechanisms of how such memories are deposited in engrams for short periods of time has received considerable attention over the past decade, the current knowledge of how memories are stored in engram cells in the long run is still scarce.
Consequently, we aim to identify the mechanisms based by which a memory becomes remote through a wide range of analyses, from morphological to biochemical and molecular aspects of engram cells. To do so, we performed contextual fear conditioning on a TRAP2 mouse model, which enables an activity-dependent genetic labeling of engram cells. For morphological changes, we analyzed dendritic spines and synapses. For biochemical changes we described the intrinsic excitability properties using patch clamp. For molecular changes, we characterized the transcriptional and epigenomic signatures with RNA-seq paired with CUT&Tag focusing on the histone post-translational modifications H3K4me3 and H3K27me3, respectively involved in gene expression and repression.
Since previous studies have indicated that memory storage cannot reside solely at the level of dendritic spines and synapses, whose turnover is too fast to account for the stability of remote memories, and since epigenetic mechanisms can stably register experience-dependent cellular activity states, we hypothesize that epigenetic mechanisms might provide a nucleus-based solution of lasting enough nature to explain the basis of long-term memories.