M1 muscarinic receptor activation reverses age-related memory updating impairment in mice

• Published in: Neurobiology of aging 2025-01, Vol.145, p.65-75
• Main Authors: Jardine, Kristen H., Minard, Emily P., Wideman, Cassidy E., Edwards, Haley, Abouelnaga, Karim H., Messer, William S., Winters, Boyer D.
• Format: Article
• Language: English
• Subjects: Acetylcholine; Aging; Aging - metabolism; Aging - physiology; Aging - psychology; Animals; Behavioural neuroscience; Male; Memory - physiology; Memory Disorders - etiology; Memory Disorders - metabolism; Memory Disorders - psychology; Memory updating; Mice, Inbred C57BL; Muscarinic receptors; Perirhinal Cortex - metabolism; Perirhinal Cortex - physiology; Receptor, Muscarinic M1 - metabolism; Receptor, Muscarinic M1 - physiology; Reconsolidation; Signal Transduction - physiology
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2024.10.007

Previously consolidated memories can become temporarily labile upon reactivation. Reactivation-based memory updating is chiefly studied in young subjects, so we aimed to assess this process across the lifespan. To do this, we developed a behavioural paradigm wherein a reactivated object memory is updated with contextual information; 3-month-old and 6-month-old male C57BL/6 mice displayed object memory updating, but 12-month-old mice did not. We found that M1 muscarinic acetylcholine receptor signaling during reactivation was necessary for object memory updating in the young mice. Next, we targeted this mechanism in an attempt to facilitate object memory updating in aging mice. Remarkably, systemic pharmacological M1 receptor activation reversed the age-related deficit. Quantification of cholinergic system markers within perirhinal cortex revealed subtle cellular changes that may contribute to differential performance across age groups. These findings suggest that natural cholinergic change across the lifespan contributes to inflexible memory in the aging brain. •Memory reactivation can signal an opportunity to update previously stored memory.•Muscarinic receptor activity gates post-reactivation object memory updating in mice.•Healthy and moderately aged mice display an object memory updating impairment.•An M1 muscarinic receptor agonist can reverse age-related memory updating deficits.