Natural Forgetting is Modulated by Experience

Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. While progress has been made in understanding the biology of engrams, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we examine whether forgetting is governed by changes in engram plasticity and suggest that it helps animals prioritize relevant memory representations for adaptive behavior. We utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. The results indicate that engram activity correlated with the rate of forgetting. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, the modulation of engram activity was able to prevent forgetting itself. Moreover, through pharmacological and behavioral interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we show that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting is an adaptive form of engram plasticity that involves circuit remodeling, which allows engrams to switch from an accessible state to an inaccessible state. ### Competing Interest Statement The authors have declared no competing interest.