Dissociating the involvement of muscarinic and nicotinic cholinergic receptors in object memory destabilization and reconsolidation

•Standard and novelty-induced object memory destabilization can be studied in mice.•mAChRs are required for destabilizing recent and remote object memories.•nAChRs are required for destabilizing recent, but not remote, object memories.•nAChRs, but not mAChRs, are required for object memory reconsolidation. The content of long-term memory is neither fixed nor permanent. Reminder cues can destabilize consolidated memories, rendering them amenable to change before being reconsolidated. However, not all memories destabilize following reactivation. Characteristics of a memory, such as its age or strength, impose boundaries on destabilization. Previously, we demonstrated that presentation of salient novel information at the time of reactivation can readily destabilize resistant object memories in rats and this form of novelty-induced destabilization is dependent upon acetylcholine (ACh) activity at muscarinic receptors (mAChRs). In the present study, we sought to determine if this same mechanism for initiating destabilization of resistant object memories is present in mice and further expand our understanding of the mechanisms through which ACh modulates object memory destabilization by investigating the role of nicotinic receptors (nAChRs). We provide evidence that in mice mAChRs are necessary for destabilizing object memories that are readily destabilized and those that are resistant to destabilization. Conversely, nAChRs were found to be necessary only when memories are readily destabilized. We then investigated the role of both receptors in the reconsolidation of destabilized object memory traces and determined that nAChRs, but not mAChRs, are necessary for object memory reconsolidation. Together, these results suggest that nAChRs may play a more selective role in the re-storage of object memories following destabilization and that ACh acts through mAChRs to act as an override signal to initiate destabilization of resistant object memories following reactivation with novelty. These findings expand our current understanding of the role of ACh in the dynamic storage of long-term memory.