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，诱导多能干细胞衍生的人脑细胞提供了 前所未有的洞察力。但是神经系统的能力来自于 因此，要将它们用作大脑病理学的模型，必须在这样的背景下进行研究， 可以像在体内一样相互影响。该领域需要具有建筑风格的传真机 重现大脑回路的排列。 研究齿状回-海马CA 3回路，该回路对记忆至关重要，并且经常在疾病中改变 例如癫痫，这个项目将把神经元和神经胶质前体细胞放置在精确的位置。项目 包括两个目标。首先，我们将创建一个适合于捕获包含单个微滴的流体微滴的矩阵。 神经胶质细胞和神经元细胞。该表面必须足够柔软以使沉积期间的细胞损伤最小化， 必须促进这些细胞的生长和它们的过程的延伸。一种多孔支架， 脑细胞外成分透明质酸是这种捕获发展的起点 衬底信号分子的嵌入将有助于指定细胞身份并促进细胞生长， 基质性质的区域调节将有助于引导细胞组织。 第二，采用细胞分选技术的方法，我们将开发一种用于光学的微流控系统， 细胞识别当含有细胞的液滴被释放时，施加电荷。当液滴福尔斯落下时 通过电压场，该电荷确定其位置。这样，细胞将被精确地沉积在 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，可重复的模型-由人类 脑细胞--神经回路功能和病理学。鉴于神经系统疾病的巨大损失， 海马体，如癫痫，抑郁症和痴呆症，改善了调查这些疾病的手段 可能的治疗方法可以使数百万个人和家庭受益。事实上，该项目将提供一个 构建微生理系统的框架，以模拟任何大脑回路。这有可能 对公众健康有重大价值。

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.