Neural mechanisms underlying memory destabilization and modification

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Great progress has been made in our understanding of memory storage in the mammalian brain. However, much remains to be discovered. Recent research has challenged the notion that long-term memory is a stable and unchanging phenomenon. Rather, memories and their biological substrates in the brain can be altered throughout life, and this modifiability probably contributes to adaptive processes required to ensure that stored information is current and relevant to ongoing behaviour. Consistent with this, our recent research has shown that rats' memories for previously encountered objects can be reactivated and modified while in a destabilized state. We have also implicated the neurotransmitter acetylcholine in these effects, showing that it is necessary for the destabilization of long-term object memories before they can become modifiable. The proposed research program will delve deeper into the mechanistic basis and behavioural implications of this phenomenon. Acetylcholine acts on a number of different receptors to exert effects in the brain. Our previous work has implicated one specific receptor sub-type (M1) in object memory destabilization. The proposed research will investigate the neuronal events following acetylcholine-induced M1 receptor activation that culminate in memory destabilization. We will use drugs to inhibit established neuronal signaling mechanisms related to M1 receptor activation in an attempt to prevent object memory destabilization in rats, thereby demonstrating the necessity of these signals for the putative memory updating process. We will also conduct similar experiments using a fear conditioning task that assesses long-term emotional memory in rats. This will enable us to study the generalizability of the mechanisms identified above. Finally, we will use a novel behavioural test for rats to perform direct analysis of the involvement of these mechanisms in measurable memory modification. Following conditions known to destabilize object memories, rats will be presented with new stimuli in an attempt to modify the destabilized information. Preliminary studies have demonstrated proof of principle with this new task, and having shown measurable memory modification, we propose to investigate the role that the above memory destabilization mechanisms play in this potentially adaptive process. Identification of a generalized memory modification mechanism would be a valuable finding from the perspective of the basic information storage functions of the mammalian brain. Furthermore, elucidation of such mechanisms will ultimately help us to better understand why and how some memories change and others do not, information that could be beneficial in a number of applied settings where maladaptive and persistent emotional memories significantly disrupt daily life (e.g., phobias, post-traumatic stress disorder, age-related cognitive inflexibility).