Mechanisms of hippocampal network-targeted stimulation to rescue memory impairment due to Alzheimer's disease

补充项目摘要/摘要 这项行政补充的目的是为了我们正在进行的资助“海马区的细胞机制” 《脑刺激产生的网络神经可塑性》(R01-NS11380)是用创新的 根据正在进行的父母拨款开发的脑刺激方法，以测试他们是否以及如何拯救 阿尔茨海默病(AD)下一代啮齿动物模型TgF344-AD的记忆障碍。广告 通过影响海马体分布网络的功能而导致记忆障碍。我们的 正在进行的项目研究电刺激大脑以海马体为靶点的机制 网络可以改善其功能。通过在健康人群中进行在体同伴电生理实验 幼年成年啮齿动物和人类神经外科病例中，深度电极位于与其同源的区域 这个正在进行的项目被植入啮齿动物体内，采用高度翻译的方法来识别 关于海马体网络如何对大脑刺激作出反应的物种。这种方法因此增强了 啮齿动物体内和体外电生理提供的机械洞察力与人体功能的相关性 为正在进行的项目进行的实验。这一行政副刊将扩大我们的翻译 解决阿尔茨海默病记忆障碍的海马区网络脑刺激模型。我们首先会 行为特征年轻(5-6个月)年龄(20-23个月)F344野生型和老年TgF344-AD大鼠(a 采用空间Morris水迷宫任务。老年F344大鼠将根据以下各项进行分类 将这项任务分为年龄未受损(AU)和年龄受损(AI)亚组，以便进行比较 在四组(年轻、AU和AI F344大鼠和老年TgF344-AD大鼠)中，将能够区分 基于衰老、典型的衰老相关记忆障碍和AD的刺激效果的变化 病理学。在每一组中，我们将比较锁定刺激和正在进行的刺激的效果 海马theta节律在海马网上的时相(与非锁相控制条件相比) 在活体电生理学和配对联想学习(PAL)触摸屏任务上的表现，这 在啮齿动物和人类中都依赖于海马体。将使用跨组比较来确定 锁相刺激是否对海马网、电生理和PAL有最大益处 TgF344-AD大鼠相对于AI大鼠的表现，AI和AU组之间以及AI和AU组之间的比较 Au和年轻的小组用来区分AD的影响和有记忆的衰老和没有记忆的衰老的影响 减损。值得注意的是，尽管脑刺激已经显示出对衰老中的记忆障碍的适度疗效 和AD，有关机制的数据很少。因此，这些实验将产生重要的和 以海马网为靶点的脑刺激如何影响动物海马网功能的新数据 使用AD。结果将有助于为人类AD患者量身定制脑刺激以挽救记忆，因为 我们开发的实验动物脑刺激模型的高度平移性。

Supplement Project Summary/Abstract The purpose of this administrative supplement for our ongoing grant “Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation” (R01-NS11380) is to use the innovative translational brain stimulation methods developed under the ongoing parent grant to test whether and how they rescue memory impairments in the next-generation rodent model of Alzheimer’s disease (AD), TgF344-AD. AD produces memory impairment by affecting the function of the distributed network of the hippocampus. Our ongoing project investigates the mechanisms whereby electrical brain stimulation targeting the hippocampal network can improve its function. By performing companion in vivo electrophysiological experiments in healthy young adult rodents and in human neurosurgical cases with depth electrodes in regions homologous to those implanted in the rodents, the ongoing project takes a highly translational approach to identify similarities across species in how the hippocampal network responds to brain stimulation. This approach thereby enhances the relevance to human function of the mechanistic insights offered by rodent in vivo and in vitro electrophysiology experiments performed for the ongoing project. This administrative supplement will expand our translational model of hippocampal network brain stimulation to address memory impairment due to AD. We first will behaviorally characterize young (5-6 mo.) and aged (20-23 mo.) F344 wild-type and aged TgF344-AD rats (a rodent model of AD) using the spatial Morris water maze task. Aged F344 rats will be categorized based on performance of this task into age-unimpaired (AU) and age-impaired (AI) subgroups, such that comparisons among the four groups (young, AU, and AI F344 rats and aged TgF344-AD rats) will be able to differentiate variation in stimulation efficacy based on aging, on typical aging-related memory impairment, and on AD pathology. In each of these groups, we will then compare the effects of locking stimulation to the ongoing phase of the hippocampal theta rhythm (versus non-phase-locked control conditions) on hippocampal network in vivo electrophysiology and on performance on the paired associate learning (PAL) touchscreen task, which is hippocampal dependent in both rodents and humans. Across-group comparisons will be used to determine whether phase-locked stimulation is maximally beneficial for hippocampal network electrophysiology and PAL performance in TgF344-AD rats relative to AI rats, with comparisons between AI and AU groups and between AU and young groups used to differentiate the effects of AD from those of aging with versus without memory impairment. Notably, although brain stimulation has shown moderate efficacy for memory impairment in aging and AD, very little data are available regarding mechanisms. These experiments will thus yield important and highly novel data on how brain stimulation targeting the hippocampal network influences its function in animals with AD. Results will be useful in tailoring brain stimulation for memory rescue in human AD patients owing to the highly translational nature of the experimental animal brain stimulation model that we have developed.