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

项目摘要(摘要) 阿尔茨海默病(AD)是一种进行性神经系统疾病，会削弱我们的大脑和记忆。最重要的 自我感觉丧失，区分不同环境和记忆的能力也受到损害 这些病人。目前，阿尔茨海默病在美国影响着500万人，它正在给健康带来巨大的负担 医疗保健系统(&GT；1000亿美元)。尽管在发现分子和细胞方面取得了重大进展 关于AD的发病机制，目前尚缺乏适当的治疗方法。还没有进行过明确的研究来 研究阿尔茨海默病患者大脑回路的变化。通过了解哪种类型的神经元活动 并证明了功能失调的神经网络和认知缺陷之间的关系，我们 可以开发有针对性的新疗法，重新激活AD患者的这些活动。 我们实验室一直在用电生理学方法研究AD模型小鼠的脑活动障碍 录制方法。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 接收来自多个皮质区域的输入，并将投影发送到海马体。脑组织中的CA1细胞 海马体将轴突送回EC，从而形成EC-海马环路。此连接 两个大脑区域之间参与了记忆的形成和提取，而这一回路的损伤导致了 记忆力受损。对AD患者和动物模型的组织学和成像研究表明， EC是AD早期萎缩和活性丧失的主要部位。然而，目前仍不清楚是哪种类型的 在阿尔茨海默病患者的EC中，甚至在AD小鼠模型中，都失去了活性。 使用一种新的淀粉样前体蛋白(APP)敲入小鼠模型，我们发现大脑网络活动称为 在EC(MEC)的内侧部分，伽玛振荡受到损害。此外，我们还获得了初步数据 表明MEC神经元被称为网格细胞，这是一种含有空间记忆相关活动的细胞类型，受到了损害 在应用程序中敲入鼠标。海马体中另一种与记忆相关的神经元--位置细胞也受到了损害。 通过光遗传操作内侧内嗅觉皮质的主要神经元，我们将重新激活 网状细胞活动受损，并测试APP敲入小鼠受损的空间记忆能否被挽救。这将是 是第一个证明细胞类型特异性电疗法是否可以是一种有效手段的研究 它还将为在各种AD小鼠模型中进行进一步的研究创造机会 作为潜在的临床转化为患者的研究。

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.