Understanding the role of gamma oscillations underlying entorhinal cortex dysfunction in Alzheimer’s disease

摘要 阿尔茨海默病(AD)是痴呆症最常见的形式。它目前影响着美国的500万人， 预计到2050年，这一数字将上升到惊人的1600万。AD不仅剥夺了患者的 基本的精神功能，但严重打击了家人和照顾者。它目前的成本估计为236美元。 10亿美元，到2050年可能会增加到1万亿美元以上。随着我们的社会迅速老龄化，对 与AD作斗争迫在眉睫。对AD患者和动物模型的组织学和影像研究表明， 内嗅皮层是AD早期萎缩和活动丧失的主要部位。然而，它仍然是 在AD早期，很大程度上不清楚内嗅皮层失去了哪种类型的活动。使用体内神经生理学 记录方法，我们最近演示了伽马振荡，反映了网络活动的总和 阿尔茨海默病模型小鼠的内嗅皮层神经元膜电位受损。我们的结果和 最近的文献表明，内脏伽马振荡可以用于生物标记物和 阿尔茨海默病的治疗靶点。在这里，我们建议研究内嗅器的伽马振荡的作用。 用AD小鼠模型研究记忆损伤中的皮层。我们的方法包括活体记录局部场 电位(Theta和Gamma振荡)和尖峰活动，光发生和化学发生方法，闭合 环路刺激、神经元丢失的细胞类型特异性组织学分析和一种新的APP敲入小鼠 模特。有三个具体目标：(目标1)确定内嗅皮层(EC)的范围和时程 伽马损伤；(目标2)确定是否使用伽马刺激重新激活网络活动 EC减轻或消除APP-KI小鼠的记忆损伤，以及(3)确定潜在的细胞类型 欧共体伽马损伤。如果成功，我们的研究将确定记忆的活体网络机制 阿尔茨海默病的损害，并将有助于确定神经元活动作为治疗目标，以防止或减缓 疾病的发展。此外，我们的研究将帮助我们开发更有效和更安全的程序 脑深部刺激作为保存或改善记忆功能的有力工具，最终可能会被使用 以减缓AD患者记忆减退的速度。

Abstract Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the US, a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic mental functions, but severely batters families and caregivers. Its costs are currently estimated at $236 billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need for combating AD is pressing. Histological and imaging studies in AD patients and animal models have shown that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. However, it is still largely unclear what type of activity is lost in the entorhinal cortex in early AD. Using in vivo neurophysiological recording methods, we recently demonstrated that gamma oscillations, a network activity reflecting summed neuronal membrane potentials, are impaired in the entorhinal cortex of an AD mouse model. Our results and recent literature suggest a possibility that entorhinal gamma oscillations can be used for both a biomarker and a therapeutic target of AD. Here we propose studies to investigate the role of gamma oscillations of entorhinal cortex in memory impairments using AD mouse models. Our approach involves in vivo recording of local field potentials (theta and gamma oscillations) and spike activity, optogenetic and chemogenetic methods, closed- loop stimulation, cell-type specific histological analyses of neuronal loss and a novel APP knock-in mouse model. There are three Specific Aims: (Aim 1) identify the extent and time course of entorhinal cortex (EC) gamma impairments; (Aim 2) determine whether the reactivation of network activity using gamma stimulation of EC attenuates or eliminates memory impairments in APP-KI mice, and (3) determine cell types that underlie the EC gamma impairment. If successful, our studies will identify in vivo network mechanisms of memory impairment in AD, and will help identify neuronal activities as therapeutic targets to prevent or slow the progression of disease. Furthermore, our study will help us develop more effective and safer procedures for deep-brain stimulation as a powerful tool to preserve or improve memory function that may eventually be used to slow the rate of memory decline in AD patients.