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.

项目摘要/摘要 某些记忆定义是健康衰老的自然部分，但在许多与年龄有关的大脑中可能很严重 疾病，包括阿尔茨海默氏病（AD）。考虑到这些缺陷可能对 患者及其家人，以及我们的人口正在老龄化的事实，迫切需要确定新的 打击与年龄和疾病相关的记忆的方法定义。一种承诺潜在的方法使用 迷走神经刺激（VNS），被认为可以通过激活轨迹来增强记忆能力 COERULEUS（LC）-Norepinephrine（NE）系统。但是，确切的VN如何影响LC-NE系统，以及如何 这些效果与增强记忆有关，尤其是在主要大脑中。 知识差距是有问题的，因为LC是最早在AD中降解的大脑区域之一 通常，随着衰老的衰老，大小和神经元数往往会下降。那就建立VN作为可行的治疗 对于年龄和广告相关的记忆，定义的定义需要首先了解其对完整和的依赖性 潜在退化的LC。这项研究的目的是建立对VNS如何影响的新理解 通过使用恒河猴作为模型系统的年轻和老年大脑中的LC-NE激活记忆 用于详细探讨基本机制。为了实现这一目标，我们将VN与神经记录配对 LC和首先专注于识别VN的模式（例如，关于时间，频率和持续时间 刺激）最有效地激活LC。然后，我们将VN与猴子中的LC录音结合在一起 他们执行助记符相似性任务，这是在人类中展示的视觉记忆任务 具有轻度认知障碍和其他形式下降形式的AD的个体。我们追求两个具体的目标。 对于AIM，我们将VNS诱导的LC神经激活模式的变化与记忆性能相关联 青少年（5-10岁）恒河猴。对于目标两个，我们将VNS诱导的神经激活变化相关联 年龄较大（18-23岁）恒河猴的记忆表现的模式。这些目标将共同提供 关于VNS如何通过LC增强记忆和两名年轻的皮质激活模式的机械洞察力 和古老的灵长类动物大脑。结果将支持VN的未来开发作为记忆缺陷的治疗 在包括AD在内的与年龄有关的疾病。