Head-mounted miniature microscopes for combined calcium imaging and electrophysiological measurement of neural circuit function in deep brain regions of behaving macaques

PROJECT SUMMARY A consensus has emerged in the Neurosciences over the last decade regarding the critical importance of understanding brain function at the level of neural circuits. Such an understanding can help us bridge across scales of investigation to provide a more comprehensive model of brain function, while also providing a more direct link to the dysfunctions associated with neurological disease. Inscopix, through its flagship product, nVista, in part facilitated by previously awarded NIH/NIMH Brain Initiative SBIR grants, is now providing neuroscientists in over 300 labs worldwide with the ability to monitor cellular-resolution, large-scale calcium dynamics in freely behaving rodents, leading to breakthrough research on the neural circuit mechanisms underlying basic behaviors. Nevertheless, to advance our understanding of higher-cognitive function, complex behavior and mental health, a critical need remains to translate such capabilities to research using non-human primates (NHPs), a model with a behavioral repertoire and brain structure similar to that of humans. In this Fast-Track proposal, we will build on our prior successful SBIRs and the success of nVista for rodents, and develop and commercialize a first-of-its-kind platform for NHP neural circuits research, enabling large- scale optical and electrophysiological (ephys) recordings deep and distributed in the brain and, critically, doing so with a streamlined surgical workflow and plug-n-play operation to aid mass adoption in labs across the world, creating new capabilities for studying human-relevant cognition, behavior and mental disorder. In Phase 1 we will design and fabricate prototypes of new probes and implant hardware, which will include virus-coated lenses, integrated baseplates and a cranial chamber system for a streamlined surgical workflow (Aim 1), together with longer lenses for deeper brain imaging, electrode-integrated lenses for same-site imaging and ephys, and a new baseplate supporting longitudinal tracking of neurons (Aim 2). We, along with two beta lab partners, will validate performance of these prototypes in NHPs (Aim 3). In Phase 2, we will design and fabricate a fully integrated hardware and software NHP platform for multi-system, simultaneous imaging and ephys (Aim 4) and fabricate 15 complete, user-friendly systems, incorporating feedback from Phase 1 and enhancing key features to enable a larger set of scientific use cases (Aim 5). We will perform extensive in vivo experiments with a larger set of beta sites to demonstrate the scientific value of all features (Aim 6). At the end of Phase 2, we will have a new platform for streamlined, fully integrated calcium imaging and ephys in deep brain regions of behaving NHPs. This platform will be the first-of-its-kind for neural circuits research in NHPs, fully designed and validated to meet the unique needs of the NHP neuroscience research community. This will allow them to ask new questions about the neural circuit mechanisms underlying perception, higher-cognitive function and complex behavior, as well as the neural circuit abnormalities underlying neurodegenerative and neuropsychiatric disease, which together will greatly advance our understanding of human mental health.PROJECT NARRATIVE The neural circuit mechanisms underlying complex cognition and behavior is of critical importance toward understanding brain function in health and disease, and, therefore, the development and dissemination of technologies that allow measurement of large-scale brain circuits has become a primary focus of NIH’s BRAIN Initiative. In this Fast-Track Proposal, we will build on our prior success in commercializing a head-mounted miniaturized microscope-based system enabling recordings of large-scale neural dynamics at single-cell resolution in freely behaving rodents, and transform it into a next-generation platform for simultaneous imaging and electrophysiology, specifically designed and validated for large-scale neural recordings in deep brain circuits of nonhuman primates, an animal model with similar brain structure, physiology and behavioral patterns to humans. This new platform will enable researchers around the world, both in academic research labs and in Pharma and Biotech, to study the neural circuit mechanisms of complex human- and clinically- relevant brain function, which will in turn lead to the development of new circuit-based therapeutics for neurodegenerative and neuropsychiatric disease.