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

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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.