Optimization, application, and dissemination of imaging modules for high-speed mesoscopic volumetric recording of neuroactivity in scattering brains

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Project Summary / Abstract A number of recent observations suggest that complex brain functions in the mammalian brain emerge from highly parallel computation in which information about sensory inputs, internal states, and behavioral parameters are mapped onto highly distributed brain-wide neuronal populations. This calls for neurotechnologies that allow for large-scale recording of neuro-activity across tissue depths and brain regions at physiological timescales and cellular resolution in awake and behaving animals. While recent advancements in optical tool development based on the combination of two-photon scanning fluorescence microscopy (2p M) and genetically-encoded calcium indicators (GECIs) as reporters of neuro-activity have been aimed at addressing these needs by developing faster, larger-scale, and volumetric calcium (Ca2+) imaging technologies, a fundamental unsolved challenge in this context is navigating the inherent tradeoffs between speed, resolution, and the size of the recording volume in a principled and scalable manner. Our lab has recently established criteria for such optimal recording schemes which has led to the realization of a new high-speed volumetric Ca2+ imaging approach termed Light Beads Microscopy (LBM). Through LBM, we have demonstrated fluorescence lifetime limited volumetric recording of neuro-activity at a single-cell resolution of up to 1 million neurons within both cortical hemispheres of awake, behaving mice. In this project, we will pursue a multipronged strategy towards the optimization, biological applications, and effective dissemination of our LBM technology while extending its performance. This will result in a more robust, less complex, and more user-friendly version of our LBM technology. To enable its broad and effective dissemination, in the second part of the project, we will utilize feedback from our α-testers to design, build, and disseminate β-prototypes of our system that will be distributed to several end-user laboratories who will be testing and applying our LBM technology in the context of their biological questions. This β-prototype will also form the basis for commercial dissemination of our technology as well as a parallel effort for its open-source dissemination.