Cerebral organoid models for optical investigation of neural circuit dynamics in neurodegenerative diseases

阿尔茨海默病（AD）是最常见的痴呆症形式，对全球老龄化人口的医疗保健产生越来越大的影响。它是由一系列病理事件引起的，包括淀粉样蛋白在细胞外斑块中的积累和受影响细胞内tau蛋白聚集体的产生。为了了解这些过程，以及它们如何影响记忆和认知基础的神经回路的功能，小鼠模型一直是重要的工具。然而，它们也有缺点——除了需要繁殖和使用大量小鼠外，小鼠不会自然患上阿尔茨海默病，而且事实证明，很难开发出包含阿尔茨海默病所有必要方面的人类基因的小鼠模型。3D类器官模型提供了一个有吸引力的提议，它可能会大大减少对小鼠使用的需求，同时，基于人类细胞系，增加了模型与人类疾病状态的相关性。该项目的目的是将目前正在进行脑类器官模型研究的两个实验室的知识和技能转移到Schultz实验室，Schultz实验室目前正在研究AD的体内小鼠模型。脑类器官技术将从Madeline Lancaster和Selina Wray的实验室转移过来，Madeline Lancaster是脑类器官发展的关键贡献者，Selina Wray最近一直在努力制作神经退行性疾病过程的脑类器官模型。这将使舒尔茨实验室大大减少小鼠的使用，同时有助于结束衰弱的神经退行性疾病条件的研究。大脑类器官技术为推进这一领域提供了巨大的潜力——例如，通过开发来自患者的干细胞的模型，这可以个性化医疗——如果它能被传播到更广泛的神经科学界。除了减少对动物的使用外，脑类器官技术还为推进神经退行性疾病的研究提供了巨大的潜力——例如，通过开发来自患者干细胞的模型，导致个性化医疗的进步。然而，这些进步需要将类器官技术传播到更广泛的实验室，包括那些参与系统神经科学研究的实验室。这一技能和技术转让项目将促进这种传播，导致神经科学的进步和针对人类遗传学的治疗方法的发展，同时减少对使用动物疾病模型的需求。

Alzheimer's Disease (AD) is the most common form of dementia, and is having an increasing impact on healthcare in aging populations worldwide. It results from a cascade of pathological events involving accumulation of amyloid protein into extracellular plaques and the generation of tau protein aggregates within affected cells. To understand these processes, and how they affect the functioning of neural circuits underlying memory and cognition, mouse models have been important tool. However, they have drawbacks - as well as requiring the breeding and use of large numbers of mice, mice do not naturally develop AD, and it has proved difficult to develop mouse models incorporating human genes which include all necessary aspects of AD. 3D organoid models offer an attractive proposition which might drastically reduce the need for mouse usage, while, being based on human cell lines, increase the relevance of the models to human disease states. The aim of this project is to transfer knowledge and skills from two laboratories which are currently performing research on cerebral organoid models to the Schultz laboratory, who currently work with in vivo mouse models of AD. Cerebral organoid technology will be transferred from the laboratories of Madeline Lancaster, who has been a key contributor to the development of cerebral organoids, and Selina Wray, who has been at the forefront of recent efforts to make cerebral organoid models of neurodegenerative disease processes. This will enable the Schultz laboratory to substantially reduce mouse usage, while contributing to research on ending debilitating neurodegenerative disease conditions. The cerebral organoid technology offers substantial potential for advancing the field - for instance through the development of models from patient-derived stem cells which can personalise medicine - if it can be disseminated to a wider range of the neuroscience community.As well as reducing animal usage, cerebral organoid technology offers substantial potential for advancing neurodegenerative disease research - for instance through the development of models from patient-derived stem cells, leading to advances in personalized medicine. Such advances however require the dissemination of the organoid technology to a wider range of laboratories, including those involved in systems neuroscience research. This skills and technology transfer project will catalyze such dissemination, leading to advances in neuroscience and the development of therapeutics tailored to human genetics, while reducing the need for the use of animal disease models.