An Exploration of the Mechanisms of Object Memory Destabilization: Involvement of the Cholinergic and Ubiquitin Proteasome Systems

Abstract

Consolidated memories may become destabilized during reactivation, resulting in a transient state of instability, presumably for updating or maintenance. Resilient engrams, such as remote memories, are reliably destabilized with salient novelty or cholinergic receptor activation during reactivation. Moreover, protein degradation via the ubiquitin proteasome system has been linked to destabilization of fear and object location memories. Given the role of calcium in regulating proteasome activity, we hypothesized that cholinergic receptors, specifically M1 muscarinic receptors (mAChRs), are linked to the ubiquitin proteasome system via inositol triphosphate receptor (IP3R)-mediated release of intracellular calcium stores. Accordingly, we investigated these mechanisms using a modified spontaneous object recognition paradigm and microinfusions into the perirhinal cortex, a brain region strongly implicated in object processing. Indeed, we established a novel pathway linking M1 mAChRs, IP3Rs, and proteasome activity to remote object memory destabilization. This research has the potential to expand our understanding of memory modification.