PROJECT SUMMARY/ABSTRACT Certain memory deficits are a natural part of healthy aging but can be severe in numerous age-related brain disorders, including Alzheimer's Disease (AD). Given the devastating effects that these deficits can have on patients and their families, plus the fact that our population is aging, there is an urgent need to identify new approaches to combat age- and disease-related memory deficits. One promising potential approach uses vagus nerve stimulation (VNS), which is thought to enhance memory abilities via activation of the locus coeruleus (LC)-norepinephrine (NE) system. However, exactly how VNS affects the LC-NE system, and how those effects relate to memory enhancements, is not well understood, particularly in the primate brain. This knowledge gap is problematic because the LC is one of the first brain regions to degrade in AD and more generally tends to decline in size and neuron number with aging. Thus, establishing VNS as a viable treatment for age- and AD-related memory deficits requires first understanding its dependence on the intact and potentially degraded LC. The goal of this study is to establish a new understanding of how VNS affects memory via LC-NE activation in younger and older primate brains, using rhesus monkeys as a model system for probing the underlying mechanisms in detail. To achieve this goal, we pair VNS with neural recordings in LC and first focus on identifying patterns of VNS (e.g., with respect to timing, frequency, and duration of stimulation) that most effectively activate LC. We then use VNS combined with LC recordings in monkeys while they perform the Mnemonic Similarity task, a visual memory task demonstrated in humans to differentiate individuals with mild cognitive impairment and AD from other forms of decline. We pursue two specific Aims. For Aim one, we relate VNS-induced changes in LC neural activation patterns to memory performance in adolescent (age 5–10 yr) rhesus monkeys. For Aim two, we relate VNS-induced changes in neural activation patterns to memory performance in older (age 18–23 yr) rhesus monkeys. Together these Aims will provide mechanistic insights into how VNS can enhance memory via LC and cortical activation patterns in both young and old primate brains. The results will support future development of VNS as a treatment for memory deficits in age-related diseases including AD.