Cholinergic manipulations bidirectionally regulate object memory destabilization

Abstract

Consolidated memories can become destabilized and open to modification upon retrieval. Destabilization is most reliably prompted when novel information is present during memory reactivation. We hypothesized that the neurotransmitter acetylcholine (ACh) plays an important role in novelty-induced memory destabilization because of its established involvement in new learning. Accordingly, we investigated the effects of cholinergic manipulations in rats using an object recognition paradigm that requires reactivation novelty to destabilize object memories. The muscarinic receptor antagonist scopolamine, systemically or infused directly into the perirhinal cortex, blocked this novelty-induced memory destabilization. Conversely, systemic oxotremorine or carbachol, muscarinic receptor agonists, administered systemically or intraperirhinally, respectively, mimicked the destabilizing effect of novel information during reactivation. These bidirectional effects suggest a crucial influence of ACh on memory destabilization and the updating functions of reconsolidation. This is a hitherto unappreciated mnemonic role for ACh with implications for its potential involvement in cognitive flexibility and the dynamic process of long-term memory storage.

An Update on Memory Reconsolidation Updating

“…At the intracellular level, there appears to be a requirement for protein degradation at the proteasome [102, 103], protein phosphatase activity [104], CamKII [105] and nitric oxide [106, 107]. At the cell surface, there is a functional involvement of cholinergic [108] and dopaminergic receptors [109], at least for non-fear memory destabilization. Of particular relevance to fear memories are the necessity for cannabinoid CB1 receptor and calcium channel activity in the dorsal hippocampus [110] and NMDA receptor activity (specifically NR2B-containing NMDA receptors) in the basolateral amygdala [111–114].…”

Dopaminergic signalling is necessary, but not sufficient for cued fear memory destabilisation

“…A further possibility is that nefiracetam acts though cholinergic receptors, via an elevation of extracellular acetylcholine (Sakurai et al, 1998). While cholinergic receptors have not to our knowledge been studied in relation to fear memory destabilisation, activation of muscarinic acetylcholine receptors is sufficient to enhance destabilisation of object recognition memories (Stiver et al, 2015). Moreover, it is possible that activation of nicotinic acetylcholine receptors also contributes to object memory destabilisation (Stiver et al, 2015), and so the identified action of nefiracetam to elevate acetylcholine-induced currents at nicotinic acetylcholine receptors (Oyaizu and Narahashi, 1999) may contribute to the destabilisation of cued fear memories.…”

“…While cholinergic receptors have not to our knowledge been studied in relation to fear memory destabilisation, activation of muscarinic acetylcholine receptors is sufficient to enhance destabilisation of object recognition memories (Stiver et al, 2015). Moreover, it is possible that activation of nicotinic acetylcholine receptors also contributes to object memory destabilisation (Stiver et al, 2015), and so the identified action of nefiracetam to elevate acetylcholine-induced currents at nicotinic acetylcholine receptors (Oyaizu and Narahashi, 1999) may contribute to the destabilisation of cued fear memories. However, perhaps the most likely mechanism of action is via NMDA receptors, given the effect of nefiracetam to potentiate NMDA receptor currents via interaction with the glycine binding site (Moriguchi et al, 2003), allied with the evidence that activation of NMDA receptors can facilitate destabilisation (Bustos et al, 2010;Ortiz et al, 2015).…”

“…The combination of pre-reactivation modafinil and post-reactivation mifepristone had no effect on test tone freezing compared to both modafinil + vehicle and vehicle + mifepristone ( Fig. 2B; group x phase: F(2,19)=0.20, p=0.82, Given that selective agonism of D1 dopamine receptors or enhancement of dopaminergic neurotransmission did not appear to facilitate destabilisation, we adopted a broader spectrum approach, using the nootropic nefiracetam, which has effects on not only monoaminergic systems (Luthman et al, 1994), but also cholinergic signalling (Oyaizu and Narahashi, 1999) and calcium channels (Yoshii and Watabe, 1994), both of which have been implicated in memory destabilisation (Suzuki et al, 2008;Stiver et al, 2015). While the mechanism of action of nefiracetam to facilitate memory destabilisation remains unclear, we focussed again on signalling at D1 dopamine receptors, testing whether such signalling is necessary for the enhancement of memory destabilisation.…”

A novel role for cortical acetylcholine in object memory updating

“…We also use the PROMM task to investigate the neurobiological mechanisms underlying object memory updating. Previously, our group demonstrated the requirement of cholinergic signaling at M1 muscarinic receptors (mAChRs) in perirhinal cortex (PRh) for destabilization of object memories 29,30 . This effect appears to be mediated by signalling downstream of the M1 receptor, including the second messenger inositol triphosphate (IP3) and activation of the ubiquitin proteasome system (UPS), which is involved in degrading synaptic proteins and is thought to underlie destabilization at the synaptic level 14,30 .…”