Organotypic whole hemisphere models to probe structure-function in neurodevelopment and neurological disease

大脑是我们最复杂的器官，控制着从认知和情绪到运动和压力反应的一切。大脑的大部分功能是由细胞与大脑内周围局部环境的相互作用决定的。大脑微环境和脑功能之间的确切相互作用仍然没有被很好地理解，限制了我们了解大脑微环境变化何时以及如何是代偿性、修复性或病理性的。这项拟议的工作开发了一个脑组织平台，以研究不同年龄、性别、大脑区域和对不同刺激的反应的大脑微结构的变化。这项拟议工作的成功完成将为大脑微环境的变化提供新的见解，这些变化影响大脑细胞的功能，并导致疾病的发生或发展。机器学习应用于通过研究大脑微结构和功能变化而产生的数据，将用于预测大脑中依赖疾病的变化。这项研究还将通过开发经过验证的开源软件来影响教育和推广，这些软件可以广泛适用于脑、其他疾病、组织探测器或数据集以外的组织。脑微结构和脑功能之间的相互作用仍然不是很清楚，尽管脑微结构和功能之间的联系是衰老、神经和精神疾病的潜在标记物。研究这种关系是具有挑战性的--大脑微环境是动态的，在大脑内的各个区域都是可变的，而且目前的成像平台在空间和时间分辨率、访问所有大脑区域以及使用同一平台针对不同年龄或疾病模型进行定制方面都受到限制。为了解决这些目前的限制，并更深入地了解微观结构的时空变化，首席研究员将使用器官型全半球脑片(OWH)平台，该平台保留了体内细胞和细胞外的实质生理学，允许在一个切片中研究多个大脑区域，对不同的刺激做出反应，并可以为不同的年龄和物种生产。研究人员将在新提出的神经退行性变的OWH模型中使用他们建立的多粒子跟踪(MPT)技术来研究作为微结构衡量标准的扩散，并应用分子生物学和功能分析工具来确定微结构变化的相关机制。机器学习模型应用于MPT数据的专业知识将被用于建立神经网络模型，以预测功能性疾病状态。使用具有MPT和分子生物学工具的可定制的OWH脑片模型，将能够在发育和对损伤/侮辱的反应中实现对局部微结构-功能关系的高时空探测和量化。建议的平台和集成技术可以在不同的领域找到巨大的实用价值，包括神经生物学、药物输送和筛选、神经疾病、组织工程和数据科学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The brain is our most complex organ and governs everything from cognition and emotion to movement and stress response. Much of the brain’s function is determined by interactions of cells with their surrounding local environment within the brain. The precise interplay between brain microenvironment and brain function is still not well-understood, limiting our ability to know when and how changes in the brain microenvironment are compensatory, reparative, or pathological. The proposed work develops a brain tissue platform to study the changes in brain microstructure in different ages, sexes, brain regions, and in response to different stimuli. Successful completion of the proposed work will provide new insights into changes in the brain microenvironment that impact function of cells in the brain and lead to disease onset or progression. Machine learning application to the data generated via studying changes in brain microstructure and function will be used to predict disease-dependent changes in the brain. This research will also impact education and outreach through development of validated open-source software that can be broadly applicable to tissues other than the brain, other diseases, tissue probes, or datasets. The interplay between brain microstructure and brain function is still not well-understood, although connections between brain microstructure and function are prospective markers for aging, neurological, and psychiatric disorders. Investigating this relationship is challenging - the brain microenvironment is dynamic and variable region to region within the brain, and current imaging platforms are limited in spatial and temporal resolution, in access to all brain regions, and in tailoring to different ages or disease models using the same platform. To address these current limitations and to provide greater insight into the spatiotemporal changes in microstructure, the principal investigator will use an organotypic whole hemisphere brain slice (OWH) platform that retains in vivo cellular and extracellular parenchymal physiology, allows study of multiple brain regions in a single slice, is responsive to different stimuli, and can be produced for different ages and species. The investigator will use their established multiple particle tracking (MPT) technology in a newly proposed OWH model of neurodegeneration to study diffusion as a measure of microstructure and apply molecular biology and functional assay tools to identify associated mechanisms of microstructural changes. Expertise in machine learning model application to MPT data will be used to build a neural network model to predict functional disease state. The use of tailorable OWH brain slice models with MPT and molecular biology tools will enable high spatiotemporal probing and quantification of regional microstructure-function relationships in development and in response to injury/insult. The proposed platform and integrated technologies can find great utility throughout diverse fields, including neurobiology, drug delivery and screening, neurological disease, tissue engineering, and data sciences.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.