Impaired spatial memory destabilization and updating in middle-aged male mice is reversed by muscarinic receptor stimulation

Reminder cues associated with earlier learning can destabilize memories, rendering them modifiable. Memory updating deficits may occur during aging, but these have not been thoroughly explored. Cholinergic dysfunction during aging could potentially contribute to these memory updating deficits, as among its many functions, acetylcholine is critical for memory destabilization. We hypothesized that mice would display memory destabilization and updating deficits with increasing age, and that pro-cholinergic manipulations could alleviate these deficits. In the current study, we show that in young (3-months), but not middle-aged (10–15-months), male C57 mice, object location memories readily destabilize. These middle-aged mice had a significant downregulation in expression of hippocampal vesicular acetylcholine transporter (VAChT). Critically, mice at both ages could acquire and retain basic object-location memories. Moreover, pre-reactivation administration of an M1 muscarinic cholinergic receptor agonist appeared to promote memory destabilization in middle-aged mice, enabling memory updating. Finally, a brief period of enrichment yielded behavioural effects consistent with enhanced memory updating, and these were associated with elevated expression of hippocampal VAChT. This research expands our understanding of the critical involvement of cholinergic system changes in age-related cognitive deficits, highlighting an underappreciated role for cholinergic transmission in memory updating functions distinct from merely learning and remembering.