Activating M1 muscarinic cholinergic receptors induces destabilization of resistant contextual fear memories in rats

Reactivation-dependent transfer of fear memory between contexts requires M1 muscarinic receptor stimulation in dorsal hippocampus

“…Here, we targeted the dorsal CA1 with a selective M1 mAChR antagonist to block destabilization of the contextual fear memory when reactivated in the original fear conditioning chamber. The fact that pirenzepine blocked reactivation-dependent transfer of fear to the alternate context is consistent with the implication of M1 mAChRs in many forms of memory destabilization (Stiver et al, 2015,2017; Huff et al, 2022; Wideman et al, 2023; Abouelnaga et al, 2023), as well as our current hypothesis that a reconsolidation-based mechanism underlies the behavioural effect in the FRaT task. Our past work suggests that M1 mAChR activity during memory reactivation could lead to downstream activation of CaMKII and the ubiquitin proteasome system (Stiver et al, 2017; Wideman et al, 2023), consistent with a documented role for synaptic protein degradation in memory destabilization (Lee et al, 2008; Jarome et al, 2011).…”

“…Given the involvement of M1 mAChRs in the destabilization of contextual fear memories, as well as the role of the dHPC in this process (Abouelnaga et al, 2023), we predicted that the updating of contextual fear memories would also be dependent on dHPC M1 mAChR stimulation. Here, we directly antagonized these receptors in the dorsal CA1 during memory reactivation.…”

“…We hypothesized that the introduction of neutral contextual information immediately following fear memory reactivation leads to integration of such contextual information with the previously-consolidated memory, resulting in fear transfer. Moreover, given our previous report implicating dorsal hippocampal M1 mAChRs in contextual fear memory destabilization (Abouelnaga et al, 2023), we predicted that antagonizing these receptors should block the updating effect by preventing destabilization of the original contextual fear memory.…”

“…Consolidated memories can become labile upon reactivation (Nader et al, 2000; Jardine et al, 2022), and this renewed malleability is related to underlying mechanisms of synaptic destabilization (Wideman et al, 2018; Lee et al, 2008). We have recently implicated the cholinergic system in reactivation-induced destabilization of object, spatial, and contextual fear memories in rats; specifically, M1 muscarinic acetylcholine receptor (mAChR) activity appears to be necessary for destabilization of these memory types (Abouelnaga et al, 2023; Stiver et al, 2015, 2017; Huff et al, 2022; Wideman et al, 2023). Furthermore, direct integrative updating of object memories with new contextual information was similarly blocked when M1 mAChRs were antagonized prior to reactivation of the original object memory (Jardine et al, 2020).…”