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

项目总结/摘要 某些记忆缺陷是健康老龄化的自然部分，但在许多与年龄相关的大脑中可能很严重。 疾病，包括阿尔茨海默病（AD）。考虑到这些赤字可能对 病人和他们的家人，加上我们的人口正在老龄化，迫切需要确定新的 治疗与年龄和疾病相关的记忆缺陷的方法。一种有希望的潜在方法是使用 迷走神经刺激（VNS），被认为通过激活该位点来增强记忆能力 蓝斑（LC）-去甲肾上腺素（NE）系统。然而，VNS究竟如何影响LC-NE系统，以及如何 这些影响与记忆增强有关，但还没有得到很好的理解，特别是在灵长类动物的大脑中。这 知识差距是有问题的，因为LC是AD中最先退化的大脑区域之一， 一般倾向于随着年龄的增长而在尺寸和神经元数量上下降。因此，建立VNS作为一种可行的治疗方法， 对于年龄和AD相关的记忆缺陷，首先需要了解其对完整和 潜在的降级LC。本研究的目的是建立一个新的认识，如何迷走神经刺激影响 以恒河猴为模型系统，通过LC-NE激活年轻和年老灵长类动物大脑中的记忆 来详细探索潜在的机制为了实现这一目标，我们将VNS与神经记录配对， LC和第一集中于识别VNS的模式（例如，在时间、频率和持续时间方面， 刺激）最有效地激活LC。然后，我们在猴子中使用VNS结合LC记录， 他们执行记忆相似性任务，这是一项在人类身上证明的视觉记忆任务， 患有轻度认知障碍和AD的人从其他形式的下降。我们追求两个具体目标。 对于目标一，我们将VNS诱导的LC神经激活模式的变化与记忆性能联系起来， 青少年（5-10岁）恒河猴。对于目标二，我们将VNS诱导的神经激活变化 老年（18-23岁）恒河猴的记忆表现模式。这些目标将共同提供 关于VNS如何通过LC和皮质激活模式增强年轻人和成年人记忆的机制见解 和古老的灵长类大脑该结果将支持VNS作为记忆缺陷治疗的未来发展 包括AD在内的老年性疾病

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.