There is increasing awareness that aberrant neural circuit activity is a core manifestation of many neuropsychiatric diseases, including autism, schizophrenia, depression and Alzheimer's disease. This realization has opened tantalizing prospects for more powerful and precise therapeutic approaches based on retuning of abnormal circuit activity. However, we still lack crucial understanding of neural activity patterns during normal behavior and how these patterns are altered in disease. Many rodent models of human brain diseases are now available, but neuroscientists are still hindered by lack of a technology for visualizing activity in large populations of genetically identified neurons in the brains of behaving animal subjects. Inscopix, Inc. spun out of Stanford University to commercialize a miniature fluorescence microscope technology that lets neuroscientists visualize Ca2+ dynamics in up to 1200 neurons simultaneously in awake, behaving rodents at cellular resolution. The microscope is easily carried on the head of a mouse or rat, and enables continuous recording from the same group of neurons in a single animal for periods of days to weeks. Used in conjunction with genetically encoded Ca2+ indicators and our custom-designed optical microendoscope probes, the microscope enables targeting of predefined neuronal subpopulations, and entry to brain regions inaccessible to other large-scale recording technologies. In Phase I, we developed and validated a new version of the microscope that is substantially higher performing and more robust than the original Stanford prototype. Around it we built the nVista imaging system: an end-to-end solution for in vivo brain imaging that includes the miniature microscope with an integrated HD camera and electronics, and user-friendly data acquisition hardware and software. The nVista system has now been disseminated for beta testing to over 100 labs around the globe. This Phase II project will move the nVista system forward in its next steps towards marketing to the general neuroscience community, through the following aims. (1) Create a next-generation version of the nVista system for commercial dissemination. Making use of feedback from early adopters, we will refine the system's design for greater performance, reliability and ease of use, by incorporating an electronic focusing mechanism, enabling higher speed data acquisition and seamless interfacing with other data collection systems; (2) Extend the technology to rats by developing an accessory array for the nVista microscope that includes a new base plate attachment mechanism, protective head-mounted cone and cable sheathing, optical probes, and an optical data link to support commutators; and (3) Develop a next-generation data analysis platform with faster processing, customizability, and better visualization tools.
This grant will further develop and refine a revolutionary miniature microscope technology to observe and investigate the thinking, working brain in animal subjects at the level of its neural circuits (populations of brain cells that control specific functions). The technology we develop and ready for future commercialization has the potential to transform our understanding of how the brain works in health, and how it malfunctions in human brain disorders including psychiatric disorders that involve abnormalities in large-scale brain function such as schizophrenia, depression, attention-deficit disorder, and autism.