MOLECULAR MECHANISMS OF REMOTE FEAR MEMORY ATTENUATION WITHIN ENGRAM ​CELLS

Understanding the factors that facilitate the attenuation of remote memories is key to developing targeted therapeutic interventions aimed at addressing maladaptive memory persistence. Despite the extensive body of research on memory processes, there is a significant gap of literature focusing on the diminution of long-standing memory traces. Recently, our lab has identified a hippocampal recall engram that is a key player in remote memory attenuation (Khalaf et al., 2018, Science), opening an avenue for memory-relevant cell type-specific molecular investigations.
In this study, we aim to elucidate the processes at work within these engram cells. Utilising the cFos-tTA transgenic mouse model in conjunction with contextual fear conditioning and extinction training, we have labelled engrams activated at recall and post-extinction for subsequent molecular analysis. Employing single-nucleus RNA sequencing, we have pinpointed several candidate genes to be differentially expressed in these cells, including BDNF and the lysine demethylase KDM6B, an enzyme of the epigenetic machinery. The latter is of particular interest given its known role in cocaine-induced reconsolidation-updating (Zhang et al., 2018, Neuropharmacology).
Accordingly, when we over-expressed KDM6B in remote fear memory engram cells, we observed enhanced remote fear attenuation. Currently, we aim to further understand KDM6B-related molecular pathways alongside associated epigenetic alterations. Ultimately, this will aid in the understanding remote fear memory attenuation from an engram-centred perspective, as well as provide insight into potential pharmacological targets.