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

补充项目摘要/摘要 本行政补充的目的是为我们正在进行的赠款“海马的细胞机制， 脑刺激产生的网络神经可塑性”（R 01-NS 11380）是使用创新的翻译 在正在进行的父母资助下开发的大脑刺激方法，以测试他们是否以及如何拯救 下一代阿尔茨海默病（AD）啮齿动物模型TgF 344-AD中的记忆障碍。AD 通过影响海马体分布网络的功能而产生记忆障碍。我们 正在进行的项目调查的机制，电脑刺激针对海马 网络可以改善其功能。通过在健康人中进行伴随的体内电生理实验， 在年轻成年啮齿动物和人类神经外科病例中， 植入啮齿类动物，正在进行的项目采取高度翻译的方法来识别 海马网络对大脑刺激的反应。这一做法，从而提高了 啮齿动物体内和体外电生理学提供的机制见解与人类功能的相关性 为正在进行的项目进行的实验。这一行政补充将扩大我们的翻译 海马网络脑刺激模型，以解决AD引起的记忆障碍。我们首先将 行为特征年轻（5-6个月）年龄（20-23个月）F344野生型和老年TgF 344-AD大鼠（a AD的啮齿动物模型）使用空间Morris水迷宫任务。将根据以下因素对老龄F344大鼠进行分类： 将该任务的性能分为年龄未受损（Au）和年龄受损（AI）亚组， 在四组（年轻、Au和AI F344大鼠和老年TgF 344-AD大鼠）中， 基于老化、典型老化相关记忆障碍和AD的刺激功效变化 病理在每一组中，我们将比较锁定刺激和持续刺激的效果。 海马网络上海马θ节律的相位（与非锁相对照条件相比） 体内电生理学和配对关联学习（PAL）触摸屏任务的性能， 在啮齿动物和人类中都依赖于海马体。将使用组间比较来确定 锁相刺激是否对海马网络电生理学和PAL最有益 TgF 344-AD大鼠相对于AI大鼠的表现，AI和Au组之间以及 Au和年轻组用于区分AD的影响与有记忆和无记忆的老年人的影响 损伤值得注意的是，尽管脑刺激对衰老中的记忆障碍显示出适度的疗效， 和AD，很少有关于机制的数据。因此，这些实验将产生重要的， 关于针对海马网络的脑刺激如何影响其在动物中的功能的高度新颖的数据 与AD结果将有助于定制脑刺激用于人类AD患者的记忆拯救， 我们开发的实验动物脑刺激模型的高度转化性。

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.