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

海马网络靶向刺激挽救阿尔茨海默氏病记忆障碍的机制

• 批准号: 10294112
• 负责人: JOHN F DISTERHOFT
• 金额: $ 26.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294112
• 关键词: Address; Administrative Supplement; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animals; Behavioral; Brain; Companions; Data; Electrical Stimulation of the Brain; Electrodes; Electrophysiology (science); Grant; Hippocampus (Brain); Human; Impairment; Implant; In Vitro; Inbred F344 Rats; Measures; Memory; Memory impairment; Methods; Modeling; Nature; Nerve Degeneration; Neuronal Plasticity; Paired-Associate Learning; Performance; Phase; Rattus; Rodent; Rodent Model; Subgroup; Task Performances; Testing; Theta Rhythm; Variant; aged; base; comparison group; experimental study; improved; in vivo; innovation; insight; morris water maze; next generation; novel; parent grant; touchscreen; translational approach; translational model; young adult

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.

补充项目摘要/摘要 这种行政补充的目的是我们正在进行的授予“海马的蜂窝机制 大脑刺激产生的网络神经塑性”（R01-NS11380）是使用创新的翻译 在正在进行的父母赠款下开发的大脑刺激方法，以测试他们是否以及如何营救 TGF344-AD的下一代啮齿动物模型（AD）的记忆障碍。广告 通过影响海马分布式网络的功能而产生记忆障碍。我们的 正在进行的项目研究了针对海马的电脑刺激的机制 网络可以改善其功能。通过在健康中进行体内电生理实验 年轻的成年啮齿动物和人类神经外科病例中具有深度电极的区域，该区域同源 植入啮齿动物，正在进行的项目采用高度翻译的方法来确定跨越的相似之处 海马网络对脑刺激的反应如何。因此，这种方法增强了 与啮齿动物体内和体外电生理学提供的机械见解的人类功能有关 为正在进行的项目执行的实验。这种行政补充将扩大我们的翻译 海马网络脑刺激的模型，以解决由于AD引起的记忆障碍。我们首先会 在行为上是年轻人（5-6个月）和老化（20-23 mo。）F344野生型和老化的TGF344-AD大鼠（a）（a） AD的啮齿动物模型）使用空间莫里斯水迷宫任务。老年F344大鼠将根据 将此任务的执行成年（AU）和年龄障碍（AI）子组的表现，以便进行比较 在这四组（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，典型与衰老相关的记忆障碍以及AD的刺激效率变化 病理。然后，在这些组中，我们将比较锁定刺激的效果与正在进行的 海马网络上海马theta节奏的阶段（相对于非相锁对照条件） 体内电生理学以及对配对的助理学习（PAL）触摸屏任务的性能，该任务 在啮齿动物和人类中都依赖海马。跨组比较将用于确定 相锁模拟是否对海马网络电生理和PAL是否最大程度有益 相对于AI大鼠，TGF344-AD大鼠的性能，AI和AU组之间的比较 Au和Young群体用来区分AD的影响与没有记忆的衰老的影响 损害。值得注意的是，尽管大脑刺激已经显示出现代的效率，可用于衰老的记忆障碍 和AD，关于机制的数据很少。因此，这些实验将产生重要和 关于靶向海马网络如何影响动物功能的大脑刺激如何影响大脑刺激的高度新数据 与广告。结果可用于调整大脑刺激，以挽救人类广告患者的记忆。 我们开发的实验动物脑刺激模型的高度翻译性质。