The role of the locus coeruleus in vagus nerve stimulation effects on age-related memory deficits

蓝斑在迷走神经刺激中的作用对年龄相关记忆缺陷的影响

• 批准号: 10293954
• 负责人: JOSHUA I GOLD
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293954
• 关键词: Adolescent; Affect; Age; Aging; Alzheimer' s Disease; Animals; Auditory; Basic Science; Behavior; Biological Models; Brain; Brain Diseases; Brain Stem; Brain region; Caliber; Clinical; Clinical Treatment; Cognition; Dependence; Development; Disease; Electrodes; Family; Frequencies; Future; Goals; Human; Image; Individual; Intractable Epilepsy; Knowledge; Learning; Macaca mulatta; Measures; Mediating; Memory; Memory Disorders; Memory impairment; Mental Depression; Monkeys; Neck; Nerve; Neurons; Norepinephrine; Nucleus solitarius; Patients; Pattern; Performance; Phase; Population; Primates; Procedures; Process; Protocols documentation; Pupil; Research Design; Rodent; Role; System; Testing; Visual; Work; age related; base; combat; design; experimental study; healthy aging; implantation; improved; insight; locus ceruleus structure; mild cognitive impairment; minimally invasive; norepinephrine system; normal aging; novel strategies; relating to nervous system; response; transcutaneous stimulation; vagus nerve stimulation; visual memory

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.

项目总结/文摘