Innervating stackable neural organoid slices with tissue-like mesh electrodes for improved neural circuit development and characterization

具有组织样网状电极的神经支配可堆叠神经类器官切片，可改善神经回路的发育和表征

• 批准号: 2326703
• 负责人: Yubing Sun
• 金额: $ 56.45万
• 依托单位: University of Massachusetts Amherst
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2326703&HistoricalAwards=false
• 关键词: Innervating; stackable; neural; organoid; slices

Neural organoids are excellent tools to study the development of human brains, however, they do not fully represent the brain structure. It is also difficult to record neuronal activities for a long time in neural organoids. To address those challenges, in this project, a new approach will be developed to derive neural organoids that better mimic brain structures. Those improved organoids will be assembled to represent interactions between various brain regions. The second objective of this project is to incorporate tissue-like, ultra-flexible mesh electrodes into those organoids. Those mesh electrodes are known to have minimal impacts on cells and can safely monitor the electrical activities of neurons chronically. The last objective is to investigate if applying electrical stimulations to neural organoids can accelerate their maturation, which usually takes several months. Together, this project will lead to improved neural organoid models and new knowledge in human brain development. The project will also support several educational and outreach activities, including new course development, undergraduate research projects, and paid internship programs. Highly motivated regional high school, undergraduate, and graduate students from diverse backgrounds will have opportunities to engage in stem cell research, which will facilitate the recruitment and retention of students in this exciting field.Neural organoids provide a promising platform for studying brain development and diseases. However, current neural organoids are still limited by the lack of proper regionalization and electrical stimulation for functional maturation and means of chronic monitoring for developmental studies. This project aims to transcend these key limitations by developing an engineered neural organoid system that is properly regionalized and innervated with a tissue-like mesh system capable of chronic monitoring and stimulation for improved studies of circuitry development in the neocortex. The overall research goal will be accomplished through three main objectives: (1) Regionalized neural organoid that enables the thalamus-subpallium-cortex projections will be assembled by stacking - sliced thalamic organoids and sliced telencephalic organoids with dorsoventrally patterned cortex and subpallium. (2) The sliced organoids will be innervated with tissue-like, ultra-flexible mesh electrodes for forming an Engineered Assembly of Sliced Organoids (EASOs) capable of real-time feedbacking the chronic developmental state. (3) Electrical stimulators will be further integrated into the mesh system for closed-loop modulation and monitoring of the EASOs, promoting functional maturation for accelerated developmental studies. The project will deepen the fundamental understanding of neural circuitry development and facilitate organoid development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

神经器官是研究人大脑发展的出色工具，但是它们并不能完全代表大脑结构。很难在神经器官中长期记录神经元活动。为了应对这些挑战，在这个项目中，将开发一种新方法来推导更好地模仿大脑结构的神经器官。这些改进的类器官将组装，以表示各个大脑区域之间的相互作用。该项目的第二个目标是将类似组织的超虚拟网格电极掺入这些器官中。已知这些网格电极对细胞产生最小的影响，并且可以安全地通过长期监测神经元的电活动。最后一个目标是研究将电刺激应用于神经器官是否可以加速其成熟，这通常需要几个月。该项目一起将导致改善的神经器官模型和人类脑发育中的新知识。该项目还将支持几项教育和推广活动，包括新课程开发，本科研究项目和付费实习计划。 来自各种背景的积极进取的区域高中，本科生和研究生将有机会从事干细胞研究，这将有助于在这个令人兴奋的领域中招募和保留学生的招募和保留。神经器官为研究脑发育和疾病提供了有前途的平台。然而，当前的神经器官仍然受到缺乏适当的区域化和电刺激的限制，用于发育研究的慢性监测和长期监测手段。该项目旨在通过开发一种工程的神经器官系统来超越这些关键局限性，该系统被适当地进行区域化并用类似组织的网格系统支配，能够长期监测和刺激，以改善新皮层电路发展的研究。总体研究目标将通过三个主要目标来实现：（1）使丘脑 - 毛皮细胞增长的区域化神经器官将通过堆叠 - 切成薄片的丘脑类器官组装，并切成薄片的端脑训练器官，并带有背侧倾斜的patpatenned patterned cortned Cortex和suppallium。 （2）切成薄片的类器官将通过组织状的，超虚拟的网状电极支配，以形成能够实时反馈慢性发育状态的切成薄片的类型器官（EASOS）的工程组装。 （3）电刺激器将进一步整合到网格系统中，以进行闭环调制和对EASOS的监测，从而促进了加速发展研究的功能成熟。该项目将加深对神经回路发展的基本理解，并促进器官开发。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响评估标准来评估的。