Miniature, Integrated Fluorescence Microscopes for In Vivo Brain Imaging

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DESCRIPTION (provided by applicant): There is a rising emphasis today on the role of neural circuitry in neuropsychiatric disease. However we still lack crucial knowledge of both normal patterns of neural activity and how these patterns go awry in disease. Although brain researchers have already created mouse models of many human brain diseases, presently there is no technology that can visualize the activity of large numbers of individual, neurons of genetically identified types in the brains of behaving mice - ideally in multiple mice in parallel. The capacity to obtain such large-scale data sets is important towards identifying neurophysiologic signatures of brain disease and is a prerequisite for developing therapeutic means of re-tuning aberrant activity patterns. Fluorescence microscopy has key advantages for tracking neural activity. However, while conventional fluorescence microscopes offer the spatiotemporal resolution needed for imaging the brain's cellular dynamics, they neither permit studies in freely behaving mice nor are scalable for studies of large numbers of animal subjects. If fluorescence microscopes could be made small, portable, and cheap, then in principle large numbers of behaving mice could be studied in parallel. Inscopix, Inc. has spun-out of Stanford University to commercialize miniature, integrated fluorescence microscopes - imaging technology that helps neuroscientists visualize neural circuit dynamics in awake behaving mice and rats. Prototype microscopes at Stanford are already enabling imaging of cerebellar microcirculation and permitting visualization of Ca2+ dynamics within hundreds of individual neurons (over weeks in some experiments) as the animal behaves freely in a naturalistic manner. The core miniature, integrated microscope technological innovation and its promise for studying the brain and its diseases was recently featured in Nature, MIT Technology Review, and several media outlets. In Phase I Inscopix aims to develop and test a new set of prototype microscopes that are significantly higher-performing, robust and part of a user-friendly end-to-end solution for in vivo brain imaging in freely behaving rodents. Specifically, we will: (1) Desig and create a new version of our miniaturized, integrated microscope. We will further develop the core technology and incorporate several improvements to significantly enhance imaging performance and extend the capabilities for in vivo brain imaging, including: (a) Attaining spatial resolution finer than 1 ¿m over fields-of-view up to 1 mm2; (b) Developing a digital, high-speed rotary commutator enabling unsupervised, imaging studies of brain activity; (c) Creating a robust and reliable microscope housing suitable for low-cost manufacturing in large volumes. (2) Develop accompanying hardware and software for data acquisition and processing. We will create a compact and user-friendly USB-compatible box for image acquisition and microscope control along with an easy-to-use Graphical User Interface (GUI). (3) Fabricate and test 10 new miniature microscopes with accompanying peripherals. We will fabricate and internally test our new designs before distributing 10 prototypes to carefully chosen beta labs for in vivo testing and validation. By the end of Phase I we expect to have received considerable in vivo usage feedback from beta labs, laying the foundation for volume production and roll-out of a market-ready product in Phase II. PUBLIC HEALTH RELEVANCE: Modern understanding of brain disease is currently undergoing a sea change, gradually shifting away from theories that emphasize a dearth or excess of neurotransmitter, and towards more sophisticated theories in which neurons of specific types exhibit improper patterns of ensemble activity underlying aberrant human behavior. This shift is especially important for disorders such as autism, which defy simple neurochemical explanations and appear to arise from circuit-level abnormalities; for disorders for which there has been much evidence to support roles for altered neurochemistry, such as schizophrenia or depression, there is rising appreciation for the equally important roles of pathologic neural circuit dynamics in causing disease phenotypes. Inscopix will develop and commercialize an innovative imaging technology for visualizing neural activity in behaving mice - and in principle, across large numbers of subjects in parallel - helping researchers obtain some of the missing knowledge about normal and aberrant neural activity patterns in mouse models of human brain disease, a key step towards developing novel therapeutics and corrective strategies.