Tools for recording brain signaling dynamics

The brain is a three-dimensional, densely wired circuit that computes via sets of distributed cells signaling and interacting at fast timescales, through a vast diversity of molecular mechanisms. In order to understand the brain, ideally it would be possible to observe the electrical activity, and other important intra- and intercellular signaling pathways, across many cells — and ideally throughout entire brains — with sufficient spatial and temporal precision to understand how they work together to mediate brain functions, and how they go wrong in brain diseases. We are developing a number of innovations — such as new or improved fluorescent reporters of cellular signals such as voltage and calcium, ways to record neural activity and cellular signals into physical chains (for later readout by sequencing or imaging), and new robotic and nanotechnological probes — to enable such analyses of brain circuit dynamics and signals. We are also working on ways to use many fluorescent reporters at once, within single living cells, to record signals throughout a signaling network, through multiplexing strategies (e.g., spatial, temporal). We are also inventing new kinds of microscope and imaging strategy to image complex 3-D brain circuit dynamics and signals, with better speed, depth, and resolution. These tools will hopefully enable comprehensive pictures of how brain cells, and the signals within them, work together to implement computations, and how these computations go awry in brain disorder states. Such observation strategies may also provide detailed biomarkers of brain disorders, new therapeutic targets, or indicators of potential drug side effects. These technologies may, in conjunction with optogenetics, enable closed-loop brain control technologies, which can introduce information into the brain as a function of brain state (“brain co-processors”), enabling new kinds of circuit characterization tool as well as new kinds of advanced brain-repair prosthetic. To build these tools, we are developing supporting approaches such as robotic and molecular strategies for molecular design, and multidimensional directed evolution of molecular tools.