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

项目摘要/摘要 某些记忆缺陷是健康衰老的自然部分，但在许多与年龄相关的大脑中可能会很严重 疾病，包括阿尔茨海默病(AD)。考虑到这些赤字可能对 患者及其家属，再加上我们的人口正在老龄化，迫切需要确定新的 应对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)，被认为是通过激活位置来增强记忆能力 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，目前还不太清楚，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和更多疾病中最先退化的大脑区域之一 随着年龄的增长，神经元的大小和数量通常会下降。因此，建立VNS是一种可行的治疗方法 对于与年龄和AD相关的记忆缺陷，需要首先了解其对完整和 潜在降解的LC。这项研究的目标是对VNS如何影响建立一个新的理解 以恒河猴为模型系统，在年轻和老年灵长类动物脑中通过LC-NE激活记忆 用于详细探索潜在的机制。为了实现这一目标，我们将VNS与 LC并首先集中于识别VNS的模式(例如，关于定时、频率和持续时间 刺激)，最有效地激活LC。然后，我们在猴子身上使用VNS和LC记录相结合的方法 他们执行记忆相似性任务，这是一种在人类身上演示的区分视觉记忆任务 轻度认知障碍和阿尔茨海默病患者来自其他形式的下降。我们追求两个具体目标。 目的一，我们将迷走神经刺激引起的LC神经激活模式的改变与大鼠的记忆成绩联系起来。 青少年(5-10岁)恒河猴。出于第二个目的，我们将VNS引起的神经激活的变化联系起来。 年龄较大(18-23岁)恒河猴的记忆表现模式。这些目标加在一起将提供 对VNS如何通过LC和大脑皮质激活模式增强记忆的机械性见解 和古老的灵长类动物的大脑。这一结果将支持迷走神经作为治疗记忆缺陷的未来发展 与年龄相关的疾病，包括阿尔茨海默病。

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.