Natural forgetting reversibly modulates engram expression

Abstract

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.

Evidence of Active-Forgetting Mechanisms? Blocking Arachidonic Acid Release May Slow Forgetting of Sensitization inAplysia

“…Our results suggest that blocking arachidonic acid release with 4-BPB can slow the forgetting of sensitization in Aplysia , though we cannot rule out effect sizes that would be too small to regularly detect with achievable sample sizes. This finding provides qualified support for the idea that forgetting of sensitization is an active process and documents another phylum in the animal kingdom (Mollusca) in which forgetting can be manipulated through alterations in second-messenger signaling ( Liu et al, 2016 ; Zhang et al, 2018 ; Bai et al, 2022 ; O’Leary et al, 2023 ). Definitive evidence for active forgetting of sensitization will require replication and examining if enhancing arachidonic acid release can speed forgetting.…”

“…For example, in fruit flies forgetting of an olfactory memory is produced through postlearning activation of a set of dopaminergic neurons; blocking this activity forestalls forgetting and enhancing activation speeds forgetting ( Berry et al, 2012 ; Himmelreich et al, 2017 ). In addition, the Rho family of G proteins seem to play an evolutionarily conserved role in forgetting, as manipulation of Rac1 bidirectionally regulates forgetting in mice ( Liu et al, 2016 ; O’Leary et al, 2023 ) and flies ( Shuai et al, 2010 ; Zhang et al, 2018 ) and Rac2 plays a similar role in Caenorhabditis elegans ( Bai et al, 2022 ). Active forgetting mechanisms can be coupled to behavior and thus can contribute not only to spontaneous/passive forgetting but also to interference-based forms of forgetting ( Berry et al, 2018 ; Zhang et al, 2018 ) and to modulation of forgetting by sleep ( Berry et al, 2015 ).…”