Investigating spatial representation in hippocampal entorhinal circuit of knock in Alzheimer's model

项目摘要（摘要） 阿尔茨海默氏病（AD）是一种进行性神经系统疾病，使我们的思维和记忆力减弱。一 自我意识丧失，区分不同环境和记忆的能力也受到损害， 这些病人。目前，AD影响美国500万人，并对健康造成重大负担。 保健系统（> 1000亿美元）。尽管在揭示分子和细胞生物学方面取得了重大进展 尽管我们还不清楚AD病理学背后的机制，但我们仍然缺乏适当的治疗方法。尚未进行明确的研究， 研究AD患者大脑回路的变化。通过了解哪些类型的神经元活动 失去了，并展示了功能失调的神经网络和认知缺陷之间的关系，我们 可以开发新的疗法，以重新激活AD患者的这些活动。 我们的实验室一直在研究AD小鼠模型的脑活动损害， 记录方法。我们关注的是一个叫做内嗅皮层（EC）的大脑区域。EC中的神经元 接收来自多个皮层区域的输入并将投射发送到海马体。CA 1细胞在 海马将其轴突送回EC，从而形成EC-海马环路。这方面 两个大脑区域之间的神经回路参与记忆的形成和提取， 记忆受损在AD患者和动物模型中的组织学和成像研究表明， EC是AD早期萎缩和活动丧失的主要部位。不过，目前还不清楚是什么类型的 在AD患者的EC中，甚至在AD小鼠模型中， 使用一种新的淀粉样前体蛋白（APP）基因敲入小鼠模型，我们发现， γ振荡在EC的内侧部分（MEC）中受损。此外，我们还获得了初步数据， 这表明MEC神经元被称为网格细胞，一种具有空间记忆相关活动的细胞类型， 在APP基因敲入小鼠中。海马体中另一个与记忆相关的神经元--位置细胞也受到了损害。 通过光遗传学操纵内侧内嗅皮层的主要神经元，我们将重新激活 受损的网格细胞活性，并测试APP基因敲入小鼠的空间记忆是否可以被挽救。这将 这是第一个证明细胞类型特异性电化学方法是否可以作为有效手段的研究。 这将为在各种AD小鼠模型中进行更多的研究创造机会 作为对患者研究的潜在临床转化。

Project Summary (Abstract) Alzheimer’s disease (AD) is a progressive neurological disorder that debilitates our mind and memory. The very sense of self is lost and ability to distinguish between different environments and remember are also impaired in these patients. Currently, AD affects 5 million people in the US and it is creating significant burden on the health care system (> $100 billion). Despite significant advances made in uncovering molecular and cellular mechanisms behind AD pathology, we still lack the proper treatment. No clear studies have been performed to investigate the changes that occur in the brain circuits of AD. By understanding what type of neuronal activities are lost and demonstrating the relationship between the dysfunctional neural network and cognitive deficits, we can develop novel therapies targeted to reactivate these activities in AD patients. Our lab has been investigating the impairment of brain activity in the AD mouse model using electrophysiological recording methods. We are focusing on a brain region called the entorhinal cortex (EC). Neurons in the EC receive input from multiple cortical regions and send projections to the hippocampus. CA1 cells in the hippocampus send their axons back to the EC, thus, forming the EC-hippocampal loop circuit. This connection between the two brain regions is involved in memory formation and retrieval and damage to this circuit results in memory impairment. Histological and imaging studies in AD patients and animal models have shown that the EC is a primary site of atrophy and activity loss in the early phases of AD. However, it is still unclear what type of activity is lost in the EC of AD patients, or even in AD mouse models. Using a novel amyloid precursor protein (APP) knock-in mouse model, we found that brain network activity called gamma oscillations are impaired in the medial part of the EC (MEC). Furthermore, we acquired preliminary data showing that MEC neurons called grid cells, a cell type harboring spatial memory-related activity, are impaired in APP knock-in mice. Place cells, another memory-associated neurons in the hippocampus, are also impaired. By optogenetically manipulating the principal neurons in the medial entorhinal cortex, we will reactivate the impaired grid cell activity and test if the disrupted spatial memory of APP knock-in mice can be rescued. This will be the first study to demonstrate whether cell type specific electroceutical approach can be an effective means of treatment for AD and it will create opportunities for additional studies in a variety of AD mouse models as well as potential clinical translation to studies in patients.