Microphysiological System for the Human Hippocampal Dentate Gyrus-CA3 Circuit

项目摘要 为了减轻神经系统疾病的负担，诱导多能干细胞来源的人脑细胞提供 具有前所未有的洞察力的潜力。但神经系统的能力来自于相互作用 因此，要将它们用作大脑病理学的模型，必须在它们的背景下进行研究 可以相互影响，就像在体内所做的那样。这一领域需要建筑方面的传真件 重述大脑回路的安排。 研究齿状回-海马区CA3回路，这是记忆的关键，在疾病中经常改变 例如癫痫，这个项目将在精确的位置放置神经元和神经胶质前体细胞。该项目 由两个目标组成。首先，我们将创建一种适合捕获包含单个液滴的液滴的基质 神经胶质细胞和神经细胞。这种表面必须足够柔软，以最大限度地减少沉积过程中对细胞的损伤 必须鼓励这些细胞的生长和它们的过程的延长。一种多孔的脚手架，由 脑细胞外成分透明质酸是开发这种捕获的起点 底物。嵌入信号分子将有助于确定细胞身份并鼓励细胞生长，以及 矩阵性质的区域性调制将有助于指导细胞组织。 其次，采用细胞分选技术的方法，研制了一套光学微流控系统 小区标识。当含有电池的液滴被释放时，就会施加电荷。当水滴落下时 通过一个电压场，这个电荷决定了它的位置。通过这种方式，细胞将精确地沉积在 模式。 由此产生的神经元和神经胶质细胞阵列将产生一个强大的、可重复性的模型--由人类 脑细胞--神经回路的功能和病理。考虑到神经疾病造成的巨大损失 海马体，如癫痫、抑郁症和痴呆症，改进了研究这些情况的方法 可能的治疗方法可能使数百万个人和家庭受益。事实上，这个项目将提供一个 构建微生理系统的框架，以对任何大脑回路进行建模。这有可能使 为公众健康带来显著的价值。

Project Summary To reduce the burden of neurological disease, induced pluripotent stem cell-derived human brain cells offer the potential for unprecedented insight. But the capabilities of the nervous system arise from the interactions of its cells, so to use them as a model of brain pathology, they must be investigated in a context where they can reciprocally influence one another as they do in vivo. The field is in need of facsimiles with architectural arrangements that recapitulate brain circuits. To study the dentate gyrus-hippocampal CA3 circuit that is critical for memory and often altered in diseases such as epilepsy, this project will place neuronal and glial precursor cells at precise locations. The project consists of two aims. First, we will create a matrix suitable for capture of fluid droplets containing individual glial and neuronal cells. This surface must be soft enough to minimize cell trauma during deposition and must encourage the growth of these cells and extension of their processes. A porous scaffold constructed of the brain extracellular component hyaluronic acid is the starting point for development of this capture substrate. Embedding of signaling molecules will help specify cell identities and encourage cell growth, and regional modulation of matrix properties will help guide cell organization. Secondly, adapting methods from cell-sorting technology, we will develop a microfluidic system for optical cell identification. When the droplet containing the cell is released, a charge is applied. As the droplet falls through a voltage field, this charge determines its position. In this way cells will be deposited in precise patterns. The resulting array of neurons and glial cells will yield a robust, reproducible model -- composed of human brain cells -- of neural circuit function and pathology. Given the great toll of neurologic diseases involving hippocampus such as epilepsy, depression, and dementia, improved means of investigating these conditions and possible treatments could benefit millions of individuals and families. Indeed, this project will provide a framework for construction of a microphysiological system to model any brain circuit. This has potential to yield significant value to public health.