Acetylcholine: The Key to Unlocking Memories for Modification

Wideman, Cassidy
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University of Guelph

Long-term memory storage is a dynamic process requiring flexibility to ensure adaptive behavioural responding in changing environments. Indeed, memory reactivation can “destabilize” consolidated traces, leading to various forms of updating. 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 presenting salient novel information at the time of reactivation can readily destabilize resistant object memories in rats. This form of novelty-induced destabilization is dependent upon acetylcholine (ACh) activity at muscarinic receptors (mAChRs), suggesting that ACh functions as an override mechanism to promote memory destabilization. The present thesis will expand upon this work to determine if ACh serves a unique function in signalling to initiate destabilization, through M1 mAChRs and their associated mechanisms, to permit memory updating in response to reactivation conditions that favor memory updating. We begin by demonstrating that cholinergic transmission in response to salient novelty present at the time of reactivation is necessary for overcoming boundary conditions and initiating object memory destabilization in mice. We then provide evidence that ACh may selectively act through mAChRs to regulate this process, as nAChRs were found to have a more specialized role in memory reconsolidation. Next, we demonstrate that reactivation conditions favoring memory updating can promote resistant object memories to be destabilized and updated, a process which is dependent upon M1 receptors and downstream activation of calcium/calmodulin-dependent protein kinase II (CaMKII). Finally, we compared the role of M1 mAChRs to that of another established neuromodulator of memory destabilization, GluN2B-containing NMDARs. Indeed, M1 mAChRs were found to function independently of GluN2B-containing NMDARs, which had limited involvement in object memory destabilization when boundary conditions were present. Together these results provide evidence that cortical ACh is involved in the dynamic storage of long-term memories, serving as a signal to override boundary conditions to permit memory updating. This may have implications for understanding and treating conditions, such as phobias, anxiety, addiction, and age-related memory impairments, that are associated with memories that persist in an unmodifiable state and contribute to the development of maladaptive and inflexible behaviour.

Memory, Acetylcholine, Memory Destabilization, Memory Updating
Wideman, C. E., Nguyen, J., Jeffries, S. D., & Winters, B. D. (2020). Fluctuating NMDA receptor subunit levels in perirhinal cortex relate to their dynamic roles in object memory destabilization and reconsolidation. International Journal of Molecular Sciences, 22(1), 67. 10.3390/ijms22010067 >Wideman, C. E., Minard, E. P., Zakaria, J. M., Capistrano, J. D. R., Scott, G. A., & Winters, B. D. (2022). Dissociating the involvement of muscarinic and nicotinic cholinergic receptors in object memory destabilization and reconsolidation. Neurobiology of Learning and Memory, 195, 107686.