Muscarinic (M1 ) cholinergic receptor activation within the dorsal hippocampus promotes destabilization of strongly encoded object location memories.

Abstract

Following the initial consolidation process, memories can become reactivated by exposure to a reminder of the original learning event. This can lead to the memory becoming destabilized and vulnerable to disruption or other forms of modification. The memory must then undergo the protein-synthesis dependent process of reconsolidation in order to be retained. However, older and/or stronger memories resist destabilization, but can become labile when reactivated in the presence of salient novelty. We have implicated the neurotransmitter acetylcholine, acting at M1 muscarinic cholinergic receptors (mAChRs) within perirhinal cortex (PRh), in novelty-induced destabilization of remote object memories. It remains unclear, however, whether mAChRs are involved in destabilization of other forms of memory. We hypothesized that the role of M1 mAChRs previously demonstrated for PRh-dependent object memory would extend to hippocampus-dependent spatial memory. Using the object location (OL) task, which relies on the dorsal hippocampus (dHPC), we showed that (a) reactivation-dependent reconsolidation of OL memories requires protein synthesis within the dHPC; (b) destabilization of relatively weak OL memories depends on M1 mAChR activation within the dHPC; (c) salient novelty during reactivation promotes destabilization of resistant strongly encoded OL memories; (d) novelty-induced destabilization of strong OL memories requires activation of mAChRs within the dHPC; and (e) M1 mAChR activation within the dHPC in the absence of novelty during memory reactivation mimics the effect of novelty, destabilizing strongly encoded OL memories. These results implicate ACh acting at M1 mAChRs in the destabilization of dHPC-dependent spatial memories, demonstrating generalizability of this cholinergic function beyond memory for object identity. These findings therefore enhance our understanding of the dynamics of long-term memory storage and suggest implications for the treatment of human conditions such as Alzheimer's disease and aging, which are characterized by behavioral and mnemonic inflexibility.