Neuronal and glial network activity in mouse models of Alzheimer's Disease.

神经退行性疾病的患病率持续上升，预计到2024年，英国将有100万人患有痴呆症。阿尔茨海默病（Alzheimer's Disease， AD）是痴呆症的主要病因，同时也与其他病因有许多共同的病理生理机制，因此了解其发病机制是研究界的基本目标。已知有几个不同的因素与阿尔茨海默病的发展有关。疾病的一个标志是在大脑中积累功能失调的淀粉样蛋白和磷酸化的tau蛋白。从细胞的角度来看，两者都涉及最终导致神经元毒性和最终神经变性的途径。这些途径也涉及小胶质细胞和星形胶质细胞，它们通过炎症的启动和维持加剧神经退行性变。淀粉样蛋白和磷酸化tau蛋白的积累对神经元和神经胶质细胞的影响目前在细胞和分子水平上得到了更好的理解，而对于它们如何影响完整大脑的整体功能却知之甚少。为了解决阿尔茨海默氏症现有文献中的这一空白，我想在阿尔茨海默氏症小鼠模型中开发并开展旨在检测星形胶质细胞和神经元之间在网络水平上的相互作用以及它如何受到淀粉样蛋白斑块积累和磷酸化tau缠结的影响的实验。在我学习的第一年，为了准备从MPhil升读博士，我计划深入研究相关文献，并在此基础上进行实验，使我掌握项目所需的技术，并朝着我的论文目标迈出具体的一步。脑电图（EEG）和局部场电位（LFP）等电生理测量似乎为神经网络功能障碍提供了可靠的读数，并且在患有痴呆症或轻度认知障碍的人类以及这些疾病的动物模型中发生了改变。星形胶质细胞的活动不能用传统的电生理技术捕获，但可以通过钙成像捕获。因此，为了研究健康和疾病中神经元网络和星形胶质细胞活动之间的相互作用，我的目标是采用多层次的方法来研究清醒动物的电路功能，结合电生理学和钙成像。我想在实验设计的背景下开始实施这种方法，包括视觉刺激的呈现和来自初级视觉皮层（V1）和头部固定小鼠其他区域的记录，最初是在野生型中，随后是在相关的Tau/淀粉样蛋白β模型中。从技术角度来看，这将涉及将病毒注射到相关脑区，在神经元或星形胶质细胞群中表达GCaMP，随后植入光纤记录钙信号，并在附近植入LFP探针记录电信号。我期待着第一年收集到的数据能够进一步告知我研究的总体方向，最终有助于理解阿尔茨海默病中神经元和神经胶质网络是如何受到影响的。

Prevalence of neurodegenerative diseases continues to be on the rise, with 1 million people predicted to suffer from dementia by 2024 in the UK. Alzheimer's Disease (AD) is the main cause of dementia while also sharing a lot of its pathophysiology with other causes, making the understanding of its mechanism of disease a fundamental aim for the research community. Several different factors are known to be involved in the development of AD. A hallmark of disease is the accumulation in the brain of dysfunctional proteins amyloid beta and phosphorylated tau. From a cellular perspective, both are implicated in pathways culminating in neuronal toxicity and ultimately neurodegeneration. These pathways also see the involvement of microglia and astrocytes, which exacerbate neurodegeneration through the initiation and maintenance of inflammation. The impact of the accumulation of amyloid beta and phosphorylated tau on neurons and glia is currently much better understood at a cellular and molecular level, while little is known about how they affect the overall function of the intact brain. To address this gap in the existing literature on AD, I want to develop and carry out experiments aimed at detecting the interplay, at the network level, between astrocytes and neurons and how it is affected by the accumulation of amyloid beta plaques and phosphorylated tau tangles in Alzheimer's mouse models. In the first year of my study, in preparation for my upgrade from MPhil to PhD, I plan to thoroughly delve into the relevant literature, and informed by it, undertake experiments that will allow me to master the techniques needed for the project as well as take concrete steps towards my thesis goals. Electrophysiological measurements such as electroencephalograms (EEG) and local field potential (LFP) appear to offer a reliable read-out for dysfunction in neural networks and are altered in humans suffering dementia or mild cognitive impairment, as well as in animal models of these disorders. Astrocyte activity cannot be captured with by conventional electrophysiological techniques but can be captured by calcium imaging. To investigate the interplay between neuronal networks and astrocyte activity in health and disease, I therefore aim to adopt a multi-level approach to circuit function in awake animals, combining electrophysiology with calcium imaging. I would like to start implementing this approach in the context of experimental designs that include the presentation of visual stimuli and the recording from primary visual cortex (V1) and other areas of head-fixed mice, initially in wild-type and subsequently in relevant Tau/Amyloid Beta models. From a technical perspective this would involve viral injections into the relevant brain area to express GCaMP in neuronal or astrocyte populations, with subsequent implantation of an optic fiber to record calcium signals and nearby LFP probe(s) to record electrical signals. I am looking forward to the data collected in my first year to further inform the overall direction of my study to ultimately contribute to the understanding of how neuronal and glial networks are affected in Alzheimer's Disease.