Engram cell mechanism for fear memory expression and update

Abstract

Part I: Disruptive effect of random abnormal activity in the dentate gyrus on contextual memory Memory recall is a highly specific process requiring precise retrieval cues. The dentate gyrus (DG) of the hippocampus is a well-known brain structure for processing contextual and spatial memory. Studies have shown lesion or silencing of the DG impairs contextual memory encoding and recall, while overly activated DG prevents proper memory retrieval. Abnormally elevated activity in the DG is repeatedly reported in amnesic mild cognitive impairment (aMCI) patients or aged adults. The correlation between memory failure and abnormally active hippocampus seems clear, but their causal relationship or the underlying nature of such interfering activity is not yet understood. Using optogenetics in combination with a carefully controlled adeno-associated virus infection system, we were able to examine the differential effects of abnormally activated hippocampus on mice motor behavior and memory function, depending on the extent of the stimulation. We found that optogenetic stimulation of massive proportion of dorsal DG cells resulted in increase in general locomotion. Random additional activity in a sparse population of dorsal DG neurons, however, interfered with contextual memory recall without inducing hyperactivity. Our findings thus demonstrate the causal role of elevated DG activity on memory recall failure, suggesting such aberrant DG activity may relate to amnesic symptoms in aMCI patients and aged adults.

Part II: Updating of the fear memory engram after retraining Memories are modified and updated through repeated experiences. How is the update memory represented at the level of memory engram? It is not yet clear whether memory update involves the same or distinct neuronal ensemble each time the learning occurs. Using both artificial memory allocation and natural engram tagging methods, we showed that the original memory engram is no longer necessary for the recall of retrained memory. Such results were accompanied with a decrease in the reactivation probability of initially allocated engram cells during retrieval of retraining memory. We also found that although the initial memory engram loses its necessity for recall of the fear memory after repeated training, these neurons still retain the fear memory as direct activation of the same neurons was sufficient for inducing a fear response. Therefore we showed inactivation of original engram cells in the amygdala during fear memory update after retraining, suggesting the formation of a distinct memory engram as a mechanism of memory engram update.