Optimization of Clear Optically Matched Panoramic Access Channel Technique (COMPACT) for large-scale deep-brain neurophotonic interface With the advance of sensitive molecular indicators and actuators, neurophotonics has become a powerful paradigm for discovering the principles underlying neural circuit functions. However, a major obstacle of using light to study neurons located deep in the mammalian brain is the limited access depth. Even with the advance of multiphoton microscopy, the majority of implementation for imaging the mammalian brain is limited to ~ 1 mm in depth. The majority of the mouse brain still remains inaccessible to cellular resolution measurement, not to mention the brain of larger mammals. To image deep brain regions, invasive miniature optical probes are required. One key issue with these optical probes is the tiny tissue access volume which limits the number of neurons to be imaged and reduces the success rate of experiments. Towards large-scale deep-brain neurophotonic interface, we have recently developed Clear Optically Matched Panoramic Access Channel Technique (COMPACT), which can effectively increase the tissue access volume by ~ three orders of magnitude. To maximize the impact of the COMPACT platform, we propose to optimize COMPACT in three major areas. First, we will further miniaturize the implementation of COMPACT. Second, we will enable COMPACT based fiber photometry and optogenetics. For these two applications, we can further reduce the capillary diameter to 160 μm. Multiple capillaries can be inserted in the mammalian brain to create the neurophotonic interface “highway” system. This development will complement the existing paradigm of mesoscale sampling with electrode array probes by providing an optical version of whole-brain-access high-capacity recording and modulation system. Third, we will develop head-mounted two-photon COMPACT system for freely moving animal studies. To benchmark the system performance, we will carry out extensive in vivo measurement of neuronal structure and activity in the living mouse brain. Specifically, we will quantify and optimize the imaging resolution, signal-to-noise ratio, and maximum imaging depth outside capillary. Moreover, we will simplify and automate the operation procedure so that it can be easily adopted by neurobiologists. With the progress of the technology development, we will also work to broadly disseminate the COMPACT based technologies. In addition to scientific publication, we will develop a comprehensive website similar to that of the Miniscope project to include the detailed mechanical and optical design files, system calibration and alignment routines, surgical procedures, and customized control software. The ultimate goal is to make COMPACT robust, turn-key, and broadly available to transform how we use light to study mammalian brains.

The proposal is to optimize a newly developed large-scale deep-brain neurophotonic interface platform. A key advance of this platform is that it can enable ~1000x tissue access volume than existing imaging modalities for deep brain imaging. Through further optimization and engineering innovation, we will make the platform broadly useful for neuroscience studies of mammalian brain.